Istituto di Genetica Molecolare “Luigi Luca Cavalli-Sforza” – CNR
Via Abbiategrasso, 207
Tel: +39 0382 546363
Attività di ricerca
Servizio di consulenza di epidemiologia e biostatistica. Collaborazione con svariati consorzi internazionali che si occupano di studi di associazione sull’intero genoma.
Tideman JWL; Parssinen O; Haarman AEG; Khawaja AP; Wedenoja J; Williams KM; Biino G; Ding X; Kahonen M; Lehtimaki T; Raitakari OT; Cheng CY; Jonas JB; Young TL; Bailey-Wilson JE; Rahi J; Williams C; He M; Mackey DA; Guggenheim JA; UK Biobank Eye; Vision Consortium; the Consortium for Refractive Error; Myopia (CREAM Consortium)
In: JAMA ophthalmology, 139 (6), pp. 601-609, 2021.
Importance: Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. Objective: To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. Design, setting, and participants: This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. Exposures: Four refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. Main outcomes and measures: Odds ratios (ORs) of polygenic risk scores in replication samples. Results: A total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16). Conclusions and relevance: Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM.
Maffoni S; Brazzo S; De Giuseppe R; Biino G; Vietti I; Pallavicini C; Cena H
In: Nutrients, 13 (4), pp. 1117, 2021.
Background: COVID-19 pandemic has imposed a period of contingency measures, including total or partial lockdowns all over the world leading to several changes in lifestyle/eating behaviours. This retrospective cohort study aimed at investigating Italian adult population lifestyle changes during COVID-19 pandemic "Phase 1" lockdown (8 March-4 May 2020) and discriminate between positive and negative changes and BMI (body mass index) variations (ΔBMI). Methods: A multiple-choice web-form survey was used to collect retrospective data regarding lifestyle/eating behaviours during "Phase 1" in the Italian adult population. According to changes in lifestyle/eating behaviours, the sample was divided into three classes of changes: "negative change", "no change", "positive change". For each class, correlations with ΔBMI were investigated. Results: Data were collected from 1304 subjects (973F/331M). Mean ΔBMI differed significantly (p < 0.001) between classes, and was significantly related to water intake, alcohol consumption, physical activity, frequency of ""craving or snacking between meals"", dessert/sweets consumption at lunch. Conclusions: During "Phase 1", many people faced several negative changes in lifestyle/eating behaviours with potential negative impact on health. These findings highlight that pandemic exacerbates nutritional issues and most efforts need to be done to provide nutrition counselling and public health services to support general population needs.
Fan Q; Pozarickij A; Tan NYQ; Guo X; Verhoeven VJM; Vitart V; Guggenheim JA; Miyake M; Tideman JWL; Khawaja AP; Zhang L; MacGregor S; Hohn R; Chen P; Biino G; and Wedenoja J al.
In: Communications biology, 3 (1), pp. 133, 2020.
Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.
Stanford FC; Cena H; Biino G; Umoren O; Jimenez M; Freeman MP; Shadyab AH; Wild RA; Womack CR; Banack HR; Manson JE
In: Menopause (N. Y. N. Y., Online), 27 (10), pp. 1117-1125, 2020.
Objective: With the rise in obesity, there has been a concomitant increase in prescription medications associated with weight gain. The objective of this study is to quantify the magnitude of association between putative weight-promoting medications and 3-year weight change in a diverse cohort of postmenopausal women in the Women's Health Initiative (WHI). Methods: This is a prospective observational cohort study, considering 40 sites in the WHI and a cohort of seventy six thousand two hundred fifty-two postmenopausal women aged 50-79 years, with weight measured at both baseline and 3 years, in the WHI-Observational Study. Body mass index (BMI) and waist circumference (WC) were measured at baseline and 3 years. An in-clinic medication inventory identified prescribed medications, including antidepressants, beta-blockers, insulin, and/or glucocorticosteroids. Generalized linear models evaluated if intermittent or persistent use of weight-promoting drugs was associated with increased BMI and WC during a 3-year follow up. Results: Women with overweight or obesity at baseline were more likely to be taking antidepressants, beta-blockers, and/or insulin. Taking at least one putative weight-promoting medication was associated with a greater increase in BMI (0.37 vs 0.27 kg/m, P = 0.0045) and WC (1.10 cm vs 0.89 cm, P = 0.0077) over the course of 3 years compared to women not on these medications. Both BMI and WC increased with the number of weight-promoting drugs prescribed (P for trend per medication used < 0.00001 for both variables). Those who took either antidepressants or insulin, or a combination of antidepressants and beta-blockers, were most likely to have a significant increase in BMI compared to nonusers. Conclusions: Antidepressants, beta-blockers, and insulin were associated with weight gain in postmenopausal women. This information may help to inform clinical decision-making and efforts to mitigate medication-related weight gain. : Video Summary:http://links.lww.com/MENO/A617.
De Giuseppe R; Calcaterra V; Biino G; Manuelli M; Mier NR; Mantelli M; De Filippo M; Cossellu G; Cena H
Unhealthy Lifestyle and Oxidative Damage in Childhood Obesity Journal Article
In: Eating and weight disorders : EWD., 25 (2), pp. 481-486, 2020.
Purpose: Oxidized LDL cholesterol (oxLDL) has been considered as a sensor of oxidative stress (OS) in childhood obesity. We integrated and related our oxLDL existing results previously assessed in overweight/obese children to lifestyle variables to investigate OS-related lifestyle variables. Methods: 178 Caucasian children/adolescents have been evaluated and according to BMI percentiles have been classified as normal weight (BMI < 75th); overweight (BMI 75-97th) and obese (BMI > 97th). Serum oxLDL levels have been measured. The dietary habits and physical activity have been also assessed. Results: No differences between normal weight and overweight/obese children were detected according to the total score of dietary habits section. Normal weight subjects reported a higher total physical activity score (p = 0.001) compared to overweight/ obese children. No correlation between oxLDL and total dietary habits and physical activity scores was noted. Increased oxLDL in subjects drinking < 1 L/day of water (p = 0.022) and in daily consumers of chocolate drinks at breakfast (p = 0.029) was observed, while a decreased oxLDL was reported in subjects consuming a breakfast based mainly on fruits (p = 0.004). Moreover, "high-fat diet" and "always eating a dessert at the end of the meal" were correlated with increased oxLDL with a trend towards significance. As regards physical activity, no correlations were observed. Conclusions: Diet and physical activity may not have an immediate impact on OS response in children with or without obesity. Unhealthy lifestyle, including increased fat, simple sugar intake, poor water intake, emerged as external exposome predictors of OS, that may be monitored to improve health status.
Wuttke M; Li Y; Li M; Sieber KB; Feitosa MF; Gorski M; Tin A; Wang L; Chu AY; Hoppmann A; Kirsten H; Giri A; Chai JF; Sveinbjornsson G; Tayo BO; Nutile T; Fuchsberger C; Marten J; Cocca M; Ghasemi S; Xu Y; Horn K; Noce D; van der Most PJ; Sedaghat S; Yu Z; Akiyama M; Afaq S; Ahluwalia TS; Almgren P; Amin N; Arnlov J; Bakker SJL; Bansal N; Baptista D; Bergmann S; Biggs ML; Biino G; et al
In: Nature Genetics, 51 (6), pp. 957-972, 2019.
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Clark DW; Okada Y; Moore KHS; Mason D; Pirastu N; Gandin I; Mattsson H; Barnes CLK; Lin K; Zhao JH; Deelen P; Rohde R; Schurmann C; Guo X; Giulianini F; Zhang W; Medina-Gomez C; Karlsson R; Bao Y; Bartz TM; Baumbach C; Biino G; et al
In: Nature Communications, 10 (4957), 2019.
In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Manuelli M; Blundell JE; Biino G; Cena H
In: Clinical Nutrition ESPEN, 29 , pp. 160-164, 2019.
BACKGROUND: In subjects with anorexia nervosa (AN) physical exercise may cause or even prevent weight loss, body composition alterations and adaptive thermogenesis. To investigate the influence of behavioral patterns on body composition and energy expenditure in women with AN, we conducted a retrospective analysis in 62 patients with AN referring to our outpatients' clinic. MATERIALS AND METHODS: We assessed anthropometric measurement of weight, height, and BMI; body composition was assessed by bioelectrical impedance analysis; resting energy expenditure was measured through indirect calorimetry. Patients' characteristics were assessed at the time of first evaluation. RESULTS: The subjects were both restricting type (ANR, n = 39) and binge-eating/purging type (ANBP, n = 23) according to DSM-5. We observed a lower reactance (58.63 (11.9) vs. 66.5 (15.5) Ohm, p < 0.05) and higher total body water in ANR subjects. No differences were found in phase angle, fat mass or fat-free mass, nor in REE measures. Within ANR subgroup, we identified two behavioral patterns, with or without physical hyperactivity. Compared to dieting and fasting subjects, hyperactive subjects showed higher phase angle [5.6 (0.7) vs. 4.8 (0.8), p < 0.05], lower fat-free mass [82.5 (6.8) vs. 89.9 (7.5)%, p < 0.05], greater proportion of fat mass [17.5 (6.8) vs. 10.1 (7.5)%, p < 0.05] and body cell mass [46.6 (5.1) vs. 42.5 (5.5)%, p < 0.05]. Finally, hyperactive subjects had greater BMI than dieting or fasting subjects [18.2 (1.7) vs. 15.8 (1.7), p < 0.005]. CONCLUSION: With limitations due to the small sample size, hyperactive subjects show body composition and energy metabolism features that seem protective in terms of prognosis.
De Giuseppe R; Braschi V; Bosoni D; Biino G; Stanford FC; Nappi RE; Cena H
In: Nutrition & dietetics, 76 (5), pp. 560-566, 2019.
AIM: The first-line therapy for polycystic ovary syndrome (PCOS) is weight loss focussing on diet and regular exercise; measurement of diet and energy intake (EI) is important to determine associations between nutrients and health in women with PCOS. The EI underreporting (UR) is a condition characterised by reports of habitual EI that is implausibly low, compared with estimated requirements. This case-control study aims to evaluate UR in women with PCOS. METHODS: Thirty-six women with PCOS were enrolled according to the Rotterdam criteria; 37 healthy women were enrolled as controls. INCLUSION CRITERIA: age range 18-45 and body mass index ≥18.5 kg/m2 in subjects without eating disorders and/or diabetes mellitus. Nutritional assessment included: anthropometry, basal metabolic rate (BMR), weight history and physical activity assessment. Subjects completed a non-consecutive three-day dietary diary to identify energy and macronutrient intake. UR was calculated (Goldberg Index: EI/BMR). RESULTS: Although women with PCOS reported a significantly higher mean BMR than controls (P < 0.0001), their EI was lower (P < 0.001), suggesting an UR in 47.2% of women with PCOS versus 2.7% of controls (P < 0.0001). The EI from simple sugars was lower in women with PCOS than controls (P < 0.01). The protein intake was increased in controls than women with PCOS (P < 0.0001). Weight cycling was more frequent in women with PCOS (P < 0.001). Logistic regression analysis identified UR associated with PCOS (P = 0.001). CONCLUSIONS: Women with PCOS underreport foods rich in simple sugars rather than underreport their total dietary intake. These results may have implications for the interpretation of diet and health correlations in this patient population.
Noordam R; Young WJ; Salman R; Kanters JK; van den Berg ME; van Heemst D; Lin HJ; Barreto SM; Biggs ML; Biino G; Catamo E; et al
In: Journal of the American College of Cardiology, 73 (24), pp. 3118-3131, 2019.
BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms. Copyright 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Graziano F; Biino G; Bonati MT; Neale BM; Do R; Concas MP; Vaccargiu S; Pirastu M; Terradura-Vagnarelli O; Cirillo M; Laurenzi M; Mancini M; Zanchetti A; Grassi M
In: Human genetics, 138 (7), pp. 739-748, 2019.
Metabolic syndrome is a complex human disorder characterized by a cluster of conditions (increased blood pressure, hyperglycemia, excessive body fat around the waist, and abnormal cholesterol or triglyceride levels). Any of these conditions increases the risk of serious disorders such as diabetes or cardiovascular disease. Currently, the degree of genetic regulation of this syndrome is under debate and partially unknown. The principal aim of this study was to estimate the genetic component and the common environmental effects in different populations using full pedigree and genomic information. We used three large populations (Gubbio, ARIC, and Ogliastra cohorts) to estimate the heritability of metabolic syndrome. Due to both pedigree and genotyped data, different approaches were applied to summarize relatedness conditions. Linear mixed models (LLM) using average information restricted maximum likelihood (AIREML) algorithm were applied to partition the variances and estimate heritability (h2) and common sib–household effect (c2). Globally, results obtained from pedigree information showed a significant heritability (h2: 0.286 and 0.271 in Gubbio and Ogliastra, respectively), whereas a lower, but still significant heritability was found using SNPs data ( h2SNP : 0.167 and 0.254 in ARIC and Ogliastra). The remaining heritability between h2 and h2SNP ranged between 0.031 and 0.237. Finally, the common environmental c2 in Gubbio and Ogliastra were also significant accounting for about 11% of the phenotypic variance. Availability of different kinds of populations and data helped us to better understand what happened when heritability of metabolic syndrome is estimated and account for different possible confounding. Furthermore, the opportunity of comparing different results provided more precise and less biased estimation of heritability.
Karlsson Linnér R; Biroli P; Kong E; et al; Biino G; et al
In: Nature Genetics, 51 (2), pp. 245-257, 2019.
Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (vertical bar(r) over cap (g)vertical bar similar to 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
Tin A; Marten J; Halperin Kuhns VL; Li Y; Wuttke M; Kirsten H; Sieber KB; Qiu C; Gorski M; Yu Z; Giri A; Sveinbjornsson G; Li M; Chu AY; Hoppmann A; O'Connor LJ; Prins B; Nutile T; Noce D; Akiyama M; Cocca M; Ghasemi S; van der Most PJ; Horn K; Xu Y; Fuchsberger C; Sedaghat S; Afaq S; Amin N; Arnlov J; Bakker SJL; Bansal N; Baptista D; Bergmann S; Biggs ML; Biino G; Boerwinkle E; et al
In: Nature genetics, 51 (10), pp. 1459-1474, 2019.
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
Shah RL; Li Q; Zhao W; Tedja MS; Tideman JWL; Khawaja AP; Fan Q; Yazar S; Williams KM; Verhoeven VJM; Xie J; Wang YX; Hess M; Nickels S; Lackner KJ; Passinen O; Wedenoja J; Biino G; Concas MP; Uitterlinden A; Rivadeneira F; Jaddoe VWV; Hysi PG; Sim X; Tan N; Tham YC; Sensaki S; Hofman A; Vingerling JR; Jonas JB; Mitchell P; Hammond CJ; Höhn R; Baird PN; Wong TY; Cheng CY; Teo YY; Mackey DA; Williams C; Saw SM; Klaver CCW; Guggenheim JA; Bailey-Wilson JE; CREAM Consortium
In: Molecular vision, 24 , pp. 127-142, 2018.
PURPOSE: To identify genes and genetic markers associated with corneal astigmatism. METHODS: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. RESULTS: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). CONCLUSIONS: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.
Lee JJ; Wedow R; Okbay A; et al; Biino G; et al
In: Nature Genetics, 50 (8), pp. 1112-1121, 2018.
Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
Ligthart S; Vaez A; Vosa U; et al; Biino G; et al
In: Annals of Human Genetics, 103 (5), pp. 691-706, 2018.
C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
Tedja MS; Wojciechowski R; Hysi PG; Eriksson N; Furlotte NA; Verhoeven VJM; Iglesias AI; Meester-Smoor MA; Tompson SW; et al; Biino G; et al; Klaver CCW
In: Nature Genetics, 50 (6), pp. 834-848, 2018.
Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.
Pozza S; De Marchi A; Albertin C; Albano D; Biino G; Aloj D; Sconfienza LM
In: 123 (9), pp. 703-709, 2018.
PURPOSE: To assess the technical feasibility of contrast-enhanced ultrasound (CEUS) in the monitoring of non-infected long bone nonunion healing. METHODS: Twenty-five patients (16 males; mean age: 40.4 ± 11.7) with long bone nonunion were treated using surgery and mesenchymal stem cells and platelet-rich plasma. They performed CEUS up to 15 days before, 7 days, 4 and 8 weeks after treatment. To categorize the angiogenesis around the fracture site, the microvascular blood flow from CEUS was classified into four categories, depending on the portion of the investigated area that was involved in the neovascularization process: grade 0 = 0%; grade 1 = 0-30%; grade 2 = 30-70%; grade 3 = 70-100%. Nonparametric Friedman and Wilcoxon statistics were used. RESULTS: Before treatment, neovascularization was graded as 0 in 15/25 patients, as 1 in 10/25. Vascularity significantly increased over time (P < 0.001), namely: 1 (25th-75th percentile = 1-2) at 7 days; 2 (1-2) at 4 weeks; 3 (0-2) at 8 weeks. All patients but one showed early progressive increase in neovascularization well identified with CEUS at the fracture site. CONCLUSION: CEUS is a feasible method to monitor healing in patients with long bone nonunion.
De Giuseppe R; Calcaterra V; Biino G; Manuelli M; Mier NR; Mantelli M; De Filippo M; Cossellu G; Cena H
Unhealthy lifestyle and oxidative damage in childhood obesity. Journal Article
In: Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity, 2018.
PURPOSE: Oxidized LDL cholesterol (oxLDL) has been considered as a sensor of oxidative stress (OS) in childhood obesity. We integrated and related our oxLDL existing results previously assessed in overweight/obese children to lifestyle variables to investigate OS-related lifestyle variables. METHODS: 178 Caucasian children/adolescents have been evaluated and according to BMI percentiles have been classified as normal weight (BMI < 75th); overweight (BMI 75-97th) and obese (BMI > 97th). Serum oxLDL levels have been measured. The dietary habits and physical activity have been also assessed. RESULTS: No differences between normal weight and overweight/obese children were detected according to the total score of dietary habits section. Normal weight subjects reported a higher total physical activity score (p = 0.001) compared to overweight/ obese children. No correlation between oxLDL and total dietary habits and physical activity scores was noted. Increased oxLDL in subjects drinking < 1 L/day of water (p = 0.022) and in daily consumers of chocolate drinks at breakfast (p = 0.029) was observed, while a decreased oxLDL was reported in subjects consuming a breakfast based mainly on fruits (p = 0.004). Moreover, "high-fat diet" and "always eating a dessert at the end of the meal" were correlated with increased oxLDL with a trend towards significance. As regards physical activity, no correlations were observed. CONCLUSIONS: Diet and physical activity may not have an immediate impact on OS response in children with or without obesity. Unhealthy lifestyle, including increased fat, simple sugar intake, poor water intake, emerged as external exposome predictors of OS, that may be monitored to improve health status. LEVEL OF EVIDENCE: Level III, case-control analytic studies.
Stanford FC; Toth AT; Shukla AP; Pratt JS; Cena H; Biino G; Aronne LJ
In: Bariatric surgical practice and patient care, 13 (4), pp. 171-178, 2018.
Weight loss medications are effective to confer additional weight loss after bariatric surgery in the general population, but they have not been evaluated in adults 60 years of age and older. We performed a retrospective study identifying 35 patients who were ≥60 years old and had undergone Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) from 2000 to 2014, and were subsequently prescribed weight loss medications. Linear regression analyses were performed to determine beta coefficients of certain predictor variables being associated with weight loss. Patients lost weight on medications with an average body mass index (BMI) change of -2.74 kg/m2, standard deviation = 2.6 kg/m2. RYGB patients lost a greater percentage of BMI on medication than SG (SG; -1.38 +/- 1.49 kg/m2 and RYGB; -3.37 +/- 2.83 kg/m2, p = 0.0372). Patients with hypertension were less likely to lose weight on medications (β = 16.76, p = 0.004, and 95% confidence interval = 5.85-27.67). Weight loss medications are a useful treatment to confer additional weight loss in adults 60 years of age and older after RYGB and SG.
Toth AT; Gomez G; Shukla AP; Pratt JS; Cena H; Biino G; Aronne LJ; Stanford FC
In: Children (Basel), 5 (9), pp. pii: E116, 2018.
This paper presents a retrospective cohort study of weight loss medications in young adults aged 21 to 30 following Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) between November 2000 and June 2014. Data were collected from patients who used topiramate, phentermine, and/or metformin postoperatively. Percentage of patients achieving ≥5%, ≥10%, or ≥15% weight loss on medications was determined and percent weight change on each medication was compared to percent weight change of the rest of the cohort. Our results showed that 54.1% of study patients lost ≥5% of their postsurgical weight; 34.3% and 22.9% lost ≥10% and ≥15%, respectively. RYGB had higher median percent weight loss (-8.1%) than SG (-3.3%) (p = 0.0515). No difference was found in median percent weight loss with medications started at weight plateau (-6.0%) versus after weight regain (-5.4%) (p = 0.5304). Patients taking medications at weight loss plateau lost 41.2% of total body weight from before surgery versus 27.1% after weight regain (p = 0.076). Median percent weight change on metformin was -2.9% compared to the rest of the cohort at -7.7% (p = 0.0241). No difference from the rest of the cohort was found for phentermine (p = 0.2018) or topiramate (p = 0.3187). Topiramate, phentermine, and metformin are promising weight loss medications for 21 to 30 year olds. RYGB patients achieve more weight loss on medications but both RYGB and SG benefit. Median total body weight loss from pre-surgical weight may be higher in patients that start medication at postsurgical nadir weight. Participants on metformin lost significantly smaller percentages of weight on medications, which could be the result of underlying medical conditions.
Vuckovic D; Mezzavilla M; Cocca M; Morgan A; Brumat M; Catamo E; Concas MP; Biino G; Franzè A; Ambrosetti U; Pirastu M; Gasparini P; Girotto G
In: European journal of human genetics, 26 (8), pp. 1167 -1179, 2018.
Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly. Although not directly life threatening, it contributes to loss of autonomy and is associated with anxiety, depression and cognitive decline. To search for genetic risk factors underlying ARHL, a large whole-genome sequencing (WGS) approach has been carried out in a cohort of 212 cases and controls, both older than 50 years to select genes characterized by a burden of variants specific to cases or controls. Accordingly, the total variation load per gene was compared and two groups were detected: 375 genes more variable in cases and 371 more variable in controls. In both cases, Gene Ontology analysis showed that the largest enrichment for biological processes (fold > 5, p-value = 0.042) was the "sensory perception of sound", suggesting cumulative genetic effects were involved. Replication confirmed 141 genes, while additional analysis based on natural selection led to a prioritization of 21 genes. The majority of them (20 out of 21) showed positive expression in mouse cochlea cDNA and were associated with two functional pathways. Among them, two genes were previously associated with hearing (CSMD1 and PTRPD) and re-sequenced in a large Italian cohort of ARHL patients (N = 389). Results led to the identification of six coding variants not detected in cases so far, suggesting a possible protective role, which requires investigation. In conclusion, we show that this multistep strategy (WGS, selection, expression, pathway analysis and targeted re-sequencing) can provide major insights into the molecular characterization of complex diseases such as ARHL.
Cena H; Stanford FC; Ochner L; Fonte ML; Biino G; De Giuseppe R; Taveras E; Misra M
In: Eating disorders , 25 (3), pp. 216-229, 2017.
This was a retrospective, observational chart review conducted on a convenience sample of 537 outpatients, aged 16-60 years, referred to an Italian Dietetic and Nutrition University Center. The study aimed to look at the association between a history of childhood obesity and dieting behaviors with development of eating disorders (EDs) at a later age. Subjects with a history of EDs (n = 118), assessed using both self-report and health records, were compared with those with no EDs (n = 419), who were attending the clinic mainly for primary prevention of metabolic and cardiovascular risk. Logistic regression analysis was performed to assess the association of childhood-onset obesity with development of an ED at a later age. Childhood-onset obesity, gender, maternal history of eating disorders, and dieting were associated with a positive history of EDs at a later age (p < .05). It is important to raise professional awareness of early symptoms of EDs in children with a history of obesity and treat them accordingly.
Joshi PK; Pirastu N; Kentistou KA; Fischer K; Hofer E; et al; Biino G; and et al; Hayward C; Chasman D; Martin NG; Sattar N; Campbell H; Esko T; Kutalik Z; Wilson JF
In: Nature Communications, 8 (1), pp. 910, 2017.
Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
Calcaterra V; De Giuseppe R; Biino G; Mantelli M; Marchini S; Bendotti G; Madè A; Avanzini MA; Montalbano C; Cossellu G; Larizza D; Cena H
In: Journal of pediatric endocrinology and metabolism, 30 (12), pp. 1257-1263, 2017.
BACKGROUND: The association between oxidative stress (OS) and metabolic syndrome (MetS) has been reported in adults. We analyzed the relation between circulating oxidized low-density lipoproteins (Ox-LDL) and MetS in pediatric ages in order to define whether plasma Ox-LDL levels are correlated to obesity and whether oxidative damage, using serum Ox-LDL levels as a proxy, are associated with MetS. METHODS: We enrolled 178 children (11.8±2.6 years). On the basis of a body mass index (BMI) threshold, the subjects were classified as: normal weight BMI <75th percentile; overweight BMI 75-97th percentile; obese BMI >97th percentile. Patients were classified as having MetS if they met three or more of the following criteria for age and sex: BMI >97th percentile, triglyceride levels >95th percentile, high-density lipoprotein (HDL) cholesterol level <5th percentile, systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) >95th percentile and impaired glucose tolerance. RESULTS: Obese children showed increased MetS prevalence (p=0.001) and higher Ox-LDL levels compared to normal- and overweight subjects (p<0.05), with a limited relation between Ox-LDL and MetS (p=0.06). Waist-to-height ratio (W/HtR) (p=0.02), triglycerides (TG) (p=0.001) and LDL-cholesterol (p<0.001) resulted independent predictors of increased plasma Ox-LDL levels. CONCLUSIONS: Oxidative damage was correlated with a hypertriglyceridemic waist phenotype and can be a precocious marker of MetS and cardiometabolic risk in obese children.
Cena H; De Giuseppe R; Biino G; Persico F; Ciliberto A; Giovanelli A; Stanford FC
In: Springerplus, 5 (1), pp. 1467, 2016.
"The study evaluated and compared the eating habits and lifestyle of patients with moderate to severe obesity who have undergone Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG). METHODS: Food frequency (FF), food habits (FH), physical activity and life style (PA) as well as smoking habits (SH) were analyzed in 50 RYGB (25 M; aged: 24-64) and 50 SG patients (25 M; aged: 22-63) by means of a validated questionnaire, before (T0) and 6 months (T1) post bariatric surgery. A score for each section (FF, FH, PA, SH) was calculated. RESULTS: ANOVA analysis (age/sex adjusted): FF and FH scores improved at T1 (RYGB and SG: p < 0.001); PA score improved but not significantly; SH score did not change at T1 neither in RYGB nor in SG. Mixed models: FF and PA scores did not correlate with age, gender, weight, BMI, neither in RYGB nor in SG; FH score was negatively correlated both with weight (RYGB: p = 0.002) and BMI (SG: p = 0.003); SH score was positively correlated with age, in SG (p = 0.002); the correlation was stronger in females than in males (p = 0.004). CONCLUSIONS: Although dietary habits improved, patients did not change their physical activity level or their smoking habits. Patients should receive adequate lifestyle counseling to ensure the maximal benefit from bariatric surgery.
Graziano F; Grassi M; Bonati MT; Zanchetti A; Biino G
In: Nutrition, Metabolism, and Cardiovascular Diseases : Nmcd. Letter To Editor, 26 (4), pp. 359-360, 2016.
Marioni RE; Ritchie SJ; Joshi PK; Hagenaars SP; Okbay A; Fischer K; Adams MJ; Hill WD; Davies G; et al nad; Biino G; et al; Benjamin DJ
Genetic variants linked to education predict longevity. Journal Article
In: Proceedings of the National Academy of Sciences of the United States of America, 113 (47), pp. 13366-13371, 2016.
Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total ndeaths = 79,702) and ∼2.4% lower risk for fathers (total ndeaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.
Barban N; Jansen R; de Vlaming R; Vaez A; Mandemakers JJ; Tropf FC; Shen X; Wilson JF; Chasman DI; Nolte IM; et al; Biino G; et al ; Koellinger PD; den Hoed M; Snieder H; Mills MC
In: Nature Genetics, 48 (12), pp. 1462-1472, 2016.
The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
Okbay A; Beauchamp JP; Fontana MA; Lee JJ; Pers TH; Rietveld CA; Turley P; Chen GB; Emilsson V; Meddens SF; Oskarsson S; Pickrell JK; Thom K; Timshel P; et al; Biino G; et al; Benjamin DJ
In: Nature, 533 (7604), pp. 539-542, 2016.
Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
Fan Q; Verhoeven VJ; Wojciechowski R; Barathi VA; Hysi PG; Guggenheim JA; Höhn R; Vitart V; Khawaja AP; Yamashiro K; Hosseini SM; et aò; Biino G; Vaccargiu S; Fossarello M; Fleck B; Yazar S; Tideman JW; Tedja M; Deangelis MM; Morrison M; Farrer L; Zhou X; Chen W; Mizuki N; Meguro A; Makela KM
In: Nature Communications, 7 , pp. 11008, 2016.
Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Bouzigon E; Nadif R; Thompson EE; Concas MP; Kuldanek S; Du G; et al; Biino G; Dizier MH; Pin I; Matran R; Lathrop M; Pirastu M; Demenais F; Ober C
In: Clinical and Experimental Allergy , 45 (4), pp. 797-806, 2015.
"BACKGROUND: Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. OBJECTIVE: We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. METHODS: We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium. RESULTS: We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 × 10(-7) ) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10(-7) ) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values. CONCLUSIONS AND CLINICAL RELEVANCE:
This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults.
2014 John Wiley & Sons Ltd."
Tkatchenko AV; Tkatchenko TV; Guggenheim JA; et al; Biino G; et al; Williams C
In: Plos Genetics, 11 (8), pp. e1005432, 2015.
Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained (""missing heritability""). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5'-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10-4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10-3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10-3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 +/- 2.2 D, p < 1.0 × 10-4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10-4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10-4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10-4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10-4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the ""missing"" myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.
Biino G; Concas MP; Cena H; Parracciani D; Vaccargiu S; Cosso M; Marras F; D'Esposito V; Beguinot F; Pirastu M
In: Springerplus, 4 , pp. 324, 2015.
The metabolic syndrome (MetS) is a large-scale and expanding public-health and clinical threat worldwide. We investigated the determinants of MetS, assessed its prevalence and components and, estimated their genetic contribution, taking advantage of the special characteristics of Sardinian isolated populations. Inhabitants of 10 villages in Ogliastra region participated in a cross-sectional survey in 2002-2008 (n = 9,647). Blood samples, blood pressure (BP), anthropometry and, data from a standardized interview were collected. Prevalence of MetS was estimated by the direct method of standardization. Variables associated with the MetS were identified using multilevel logistic regression. Heritability was determined using variance component models. MetS Prevalence was 19.6% (95% CI 18.9-20.4%) according to NCEP-ATPIII, 24.8% (95% CI 24.0-25.6%) according to IDF and, 29% (95% CI 28.1-29.8%) according to AHA/NHLBI harmonized criteria, ranging from 9 to 26% among villages. The most prevalent combination was BP + HDL-cholesterol (HDL) + triglycerides (TRIG) (19%), followed by BP + HDL + waist circumference (WAIST) (17%) and, BP + HDL + TRIG + WAIST (13.6%). Heritability of MetS was 48% (p = 1.62 × 10(-25)), as the two most common combinations (BP + HDL + TRIG and BP + HDL + WAIST) showed heritability of 53 and 52%, respectively. The larger genetic components of the two most frequent combinations determining MetS deserve greater investigation in order to understand the underlying mechanisms. Besides, further studies are warranted to confirm these findings both in isolated and outbred populations.
Cena H; Fonte ML; Casali PM; Maffoni S; Roggi C; Biino G
In: Pediatric Obesity, 10 (2), pp. 105-111, 2015.
BACKGROUND: Obese adolescents with high proportion of visceral fat are at higher risk of developing the metabolic syndrome. OBJECTIVES: The study aims to investigate if echocardiographic epicardial fat thickness (EF) could be predictive of visceral obesity (VO) early in life and to provide EF threshold values specific for male adolescents. Further aim was to investigate the association between EF, lifestyle and metabolic disease familiarity. METHODS: Anthropometric data were collected from 102 normal weight and overweight, healthy male adolescents (mean age: 14.91 +/- 1.98 years); bioelectrical impedance analysis and transthoracic echocardiogram were performed in the same sample. Each participant fulfilled a validated self-administered lifestyle questionnaire. RESULTS: We found higher EF values in sedentary adolescents (P < 0.05), in those who never eat fruit and vegetables (P < 0.05), and in those with overweight mothers (P < 0.05). The strongest independent predictor of EF was waist circumference (P < 0.0001). Using the waist to height ratio as a marker of VO, logistic regression analysis revealed that 1 mm EF gain is responsible for seven times higher VO risk (P < 0.0001). Receiver Operating Characteristic (ROC) analysis showed that the optimal cut-off for EF thickness associated to youth VO is 3.2 mm.
Vuckovic D; Dawson S; Scheffer DI; Rantanen T; Morgan A; Di Stazio M; Vozzi D; Nutile T; Concas MP; Biino G; Nolan L; Bahl A; Loukola A; Viljanen A; Davis A; Ciullo M; Corey DP; Pirastu M; Gasparini P; Girotto G
In: Human Molecular Genetics , 24 (19), pp. 5655-5664, 2015.
Hearing loss and individual differences in normal hearing both have a substantial genetic basis. Although many new genes contributing to deafness have been identified, very little is known about genes/variants modulating the normal range of hearing ability. To fill this gap, we performed a two-stage meta-analysis on hearing thresholds (tested at 0.25, 0.5, 1, 2, 4, 8 kHz) and on pure-tone averages (low-, medium- and high-frequency thresholds grouped) in several isolated populations from Italy and Central Asia (total N = 2636). Here, we detected two genome-wide significant loci close to PCDH20 and SLC28A3 (top hits: rs78043697, P = 4.71E-10 and rs7032430, P = 2.39E-09, respectively). For both loci, we sought replication in two independent cohorts: B58C from the UK (N = 5892) and FITSA from Finland (N = 270). Both loci were successfully replicated at a nominal level of significance (P < 0.05). In order to confirm our quantitative findings, we carried out RT-PCR and reported RNA-Seq data, which showed that both genes are expressed in mouse inner ear, especially in hair cells, further suggesting them as good candidates for modulatory genes in the auditory system. Sequencing data revealed no functional variants in the coding region of PCDH20 or SLC28A3, suggesting that variation in regulatory sequences may affect expression. Overall, these results contribute to a better understanding of the complex mechanisms underlying human hearing function.
Zoledziewska M; Sidore C; Chiang CW; Sanna S; Mulas A; Steri M; Busonero F; Marcus JH; Marongiu M; Maschio A; Del Vecchyo DO; Floris M; Meloni A; Delitala A; Concas MP; Murgia F; Biino G; Vaccargiu S; Nagaraja R; Lohmueller KE; UK10K Consortium; Timpson NJ; Soranzo N; Tachmazidou I; Dedoussis G; Zeggini E; Understanding Society Scientific Group; Uzzau S; Jones C; Lyons R; Angius A; Abecasis GR; Novembre J; Schlessinger D; Cucca F
In: Nature Genetics, 47 (11), pp. 1352-1356, 2015.
We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.
Zaninetti C; Biino G; Noris P; Melazzini F; Civaschi E; Balduini CL
In: Haematologica, 100 (9), pp. e338-340, 2015.
Graziano F; Grassi M; Sacco S; Concas MP; Vaccargiu S; Pirastu M; Biino G
In: Nutrition, Metabolism, and Cardiovascular Diseases : Nmcd. Letter To Editor, 25 , pp. 548-555, 2015.
BACKGROUND AND AIMS: Owing to the multiplicity of the key components of metabolic syndrome (MetS), its diagnosis is very complex. The lack of a unique definition is responsible for the prevalence variability observed among studies; therefore, a definition based on continuous variables was recommended. The aim of this study was to compare competing models of the MetS factor structure for selecting the one that explains the best clustering pattern and to propose an algorithm for computing MetS as a continuous variable. METHODS AND RESULTS: Data were from isolated Sardinian populations (n = 8102). Confirmatory factor analysis (CFA) and two-group CFA by gender were performed to evaluate the sex-specific factor structure of MetS. After selecting the best model, an algorithm was obtained using factor loadings/residual variances. The quality of the MetS score was evaluated by the receiver operating characteristics curve and the area under the curve. Cross-validation was performed to validate the score and to determine the best cut point. The best fit model was a bifactor one with a general factor (MetS) and three specific factors (f1: obesity/adiposity trait; f2: hypertension/blood pressure trait; and f3: lipid trait). Gender-specific algorithms were implemented to obtain MetS scores showing a good diagnostic performance (0.80 specificity and 0.80 sensitivity for the cut point). Furthermore, cross-validation confirmed these results. CONCLUSION: These analyses suggested that the bifactor model was the most representative one. In addition, they provided a score and a cut point that are both clinically accessible and interpretable measures for MetS diagnosis and likely useful for evaluating the association with adverse cardiovascular disease and diabetes and for investigating the MetS genetic component.Copyright © 2015 Elsevier B.V. All rights reserved.