Publications by authors named "Tanguy Corre"

35 Publications

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Heritability and association with distinct genetic loci of erythropoietin levels in the general population.

Haematologica 2021 Sep 1;106(9):2499-2501. Epub 2021 Sep 1.

National Centre of Competence in Research "Kidney.CH", Switzerland; Institute of Physiology, University of Zurich, Zurich.

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http://dx.doi.org/10.3324/haematol.2021.278389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409065PMC
September 2021

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

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 (F) for >1.4 million individuals, we show that F 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: F 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 F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Nat Commun 2019 09 11;10(1):4130. Epub 2019 Sep 11.

Department of Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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http://dx.doi.org/10.1038/s41467-019-11576-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739370PMC
September 2019

Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals.

Sci Rep 2019 07 1;9(1):9439. Epub 2019 Jul 1.

Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.
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http://dx.doi.org/10.1038/s41598-019-45823-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602949PMC
July 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

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.
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http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

Negative effect of vitamin D on kidney function: a Mendelian randomization study.

Nephrol Dial Transplant 2018 12;33(12):2139-2145

Divisione di Nefrologia, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: The kidney plays a central role in the regulation of vitamin D metabolism. It is not clear, however, whether vitamin D influences kidney function. Previous studies have reported conflicting results, which may have been influenced by reverse causation and residual confounding. We conducted a Mendelian randomization (MR) study to obtain unconfounded estimates of the association between genetically instrumented vitamin D metabolites and estimated glomerular filtration rate (eGFR) as well as the urinary albumin:creatinine ratio (UACR).

Methods: We performed a two-sample MR study based on three single nucleotide variants associated with 25(OH)D levels: rs2282679, rs10741657 and rs12785878, related to the genes GC, CYP2R1 and DHCR7, respectively. Estimates of the allele-dependent effects on serum 25(OH)D and eGFR/UACR were obtained from summary statistics of published genome-wide association meta-analyses. Additionally, we performed a one-sample MR analysis for both 25(OH)D and 1,25(OH)2 D using individual-level data from six cohorts.

Results: The combined MR estimate supported a negative causal effect of log transformed 25(OH)D on log transformed eGFR (β = -0.013, P = 0.003). The analysis of individual-level data confirmed the main findings and also revealed a significant association of 1,25(OH)2 D on eGFR (β = -0.094, P = 0.008). These results show that a 10% increase in serum 25(OH)D levels causes a 0.3% decrease in eGFR. There was no effect of 25(OH)D on UACR (β = 0.032, P = 0.265).

Conclusion: Our study suggests that circulating vitamin D metabolite levels are negatively associated with eGFR. Further studies are needed to elucidate the underlying mechanisms.
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http://dx.doi.org/10.1093/ndt/gfy074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275146PMC
December 2018

Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes.

J Am Soc Nephrol 2018 01 1;29(1):335-348. Epub 2017 Nov 1.

Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.

Magnesium (Mg) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg, which is crucial for Mg homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (4.4×10) near , which encodes an epithelial Mg channel, and rs35929 (2.1×10), a variant of , which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg regulated the expression of the highly conserved ortholog , and knockdown resulted in renal Mg wasting and metabolic disturbances. Finally, rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg deficiency to insulin resistance and obesity.
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http://dx.doi.org/10.1681/ASN.2017030267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748908PMC
January 2018

Interaction between the gene, body mass index and depression: meta-analysis of 13701 individuals.

Br J Psychiatry 2017 08 22;211(2):70-76. Epub 2017 Jun 22.

Margarita Rivera, PhD, Department of Biochemistry and Molecular Biology II and Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain, and MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, Kinǵs College London, UK; Adam E. Locke, PhD, Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA; Tanguy Corre, PhD, Department of Medical Genetics, University of Lausanne, Lausanne, and Swiss Institute of Bioinformatics, Lausanne, Switzerland; Darina Czamara, PhD, Christiane Wolf, PhD, Max Planck Institute of Psychiatry, Munich, Germany; Ana Ching-Lopez, Department of Psychiatry, School of Medicine, University of Granada, and Institute of Neurosciences Federico Olóriz, Centra de Investigación Biomédica, University of Granada, Spain; Yuri Milaneschi, PhD, Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center/GGZ in Geest, Amsterdam, The Netherlands; Stefan Kloiber, MD, Max Planck Institute of Psychiatry, Munich, Germany; Sara Cohen-Woods, PhD, School of Psychology, Flinders University, Adelaide, South Australia, Australia; James Rucker, MD, PhD, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK; Katherine J. Aitchison, MD, PhD, Department of Psychiatry, University of Alberta, Alberta, Canada; Sven Bergmann, PhD, Department of Medical Genetics, University of Lausanne, Lausanne, and Swiss Institute of Bioinformatics, Lausanne, Switzerland; Dorret I. Boomsma, PhD, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands; Nick Craddock, MB, PhD, FMedSci, Department of Psychological Medicine and Neurology, Cardiff University School of Medicine, Henry Wellcome Building, Cardiff, UK; Michael Gill, MD, Department of Psychiatry, Trinity Centre for Health Sciences, Dublin 8, Ireland; Florian Holsboer, MD, PhD, Max Planck Institute of Psychiatry, Munich, Germany; Jouke-Jan Hottenga, PhD, Department of Psychiatry, University of Alberta, Alberta, Canada; Ania Korszun, PhD, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Zoltan Kutalik, PhD, Department of Medical Genetics, University of Lausanne, Lausanne, and Swiss Institute of Bioinformatics, Lausanne, Switzerland; Susanne Lucae, MD, PhD, Max Planck Institute of Psychiatry, Munich, Germany; Wolfgang Maier, MD, Department of Psychiatry, University of Bonn, Bonn, Germany; Ole Mors, MD, PhD, Research Department P, Aarhus University Hospital, Risskov, Denmark; Bertram Müller-Myhsok MD, Max Planck Institute of Psychiatry, Munich, Germany; Michael J. Owen, MB, PhD, FMedSci, MRC Centre for Neuropsychiatry Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK; Brenda W. J. H. Penninx, PhD, Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center/GGZ in Geest, Amsterdam, The Netherlands; Martin Preisig, MD, Department of Psychiatry, Lausanne University Hospital, 1008 Prilly-Lausanne, Switzerland; John Rice, PhD, Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, USA; Marcella Rietschel, MD, Central Institute of Mental Health, Mannheim, Germany; Federica Tozzi, MD, Genetics Division, Drug Discovery, GlaxoSmithKline Research and Development, Verona, Italy; Rudolf Uher, MD, PhD, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK, and Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; Peter Vollenweider, MD, PhD, Gerard Waeber, MD, PhD, Division of Internal Medicine, CHUV, Lausanne, Switzerland; Gonneke Willemsen, PhD, Department of Psychiatry, University of Alberta, Alberta, Canada; Ian W. Craig, PhD, Anne E. Farmer, MD, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK; Cathryn M. Lewis, PhD, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, and Department of Medical and Molecular Genetics, School of Medicine, King's College London, UK; Gerome Breen, PhD, Peter McGuffin, MB, PhD, FMedSci, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.

Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the gene, suggesting its implication in the association between depression and obesity.To confirm these findings by investigating the polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.In the replication cohorts, we observed a significant interaction between , BMI and depression with fixed effects meta-analysis (β = 0.12, = 2.7 × 10) and with the Han/Eskin random effects method ( = 1.4 × 10) but not with traditional random effects (β = 0.1, = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, = 0.027) being highly significant based on the Han/Eskin model ( = 6.9 × 10). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of This meta-analysis provides additional support for a significant interaction between , depression and BMI, indicating that depression increases the effect of on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.
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http://dx.doi.org/10.1192/bjp.bp.116.183475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537566PMC
August 2017

Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

PLoS Genet 2017 Apr 27;13(4):e1006528. Epub 2017 Apr 27.

Estonian Genome Center, University of Tartu, Tartu, Estonia.

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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http://dx.doi.org/10.1371/journal.pgen.1006528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407576PMC
April 2017

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits.

Nat Commun 2017 04 26;8:14977. Epub 2017 Apr 26.

Centre for Genetic Origins of Health and Disease, University of Western Australia, Crawley, Australia.

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
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http://dx.doi.org/10.1038/ncomms14977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414044PMC
April 2017

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Nat Genet 2017 Jun 24;49(6):834-841. Epub 2017 Apr 24.

Institute of Genetics and Biophysics, CNR, Naples, Italy.

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
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http://dx.doi.org/10.1038/ng.3841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841952PMC
June 2017

and Loci Associate with Plasma Osmolality.

J Am Soc Nephrol 2017 Aug 30;28(8):2311-2321. Epub 2017 Mar 30.

Due to the number of contributing authors, the affiliations are listed in the supplemental material.

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at <5.0 × 10 Of these, rs9980 at replicated in stage 2 meta-analysis (=3.1 × 10), with combined stages 1 and 2 genome-wide significance of =5.6 × 10 Transethnic meta-analysis further supported the association at rs9980 (=5.9 × 10). Additionally, rs16846053 at showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (=6.7 × 10). encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for and are expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in and expression and function in the central nervous system may affect the regulation of systemic water balance.
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http://dx.doi.org/10.1681/ASN.2016080892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533231PMC
August 2017

Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine.

Pflugers Arch 2017 01 3;469(1):91-103. Epub 2016 Dec 3.

Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.

The nature and importance of genetic factors regulating the differential handling of Ca and Mg by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p = 1.7 × 10), encompassing CLDN14, the gene coding for claudin-14, that was genome-wide significant when using urinary magnesium-to-calcium ratio, but not either one taken separately. In mouse, claudin-14 is expressed in the distal nephron segments specifically handling magnesium, and its expression is regulated by chronic changes in dietary magnesium content. A genome-wide approach identified common variants in the CLDN14 gene exerting a robust influence on the differential excretion of Mg over Ca in urine. These data highlight the power of urinary electrolyte ratios to unravel genetic determinants of renal tubular function. Coupled with mouse experiments, these results support a major role for claudin-14, a gene associated with kidney stones, in the differential paracellular handling of divalent cations by the renal tubule.
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http://dx.doi.org/10.1007/s00424-016-1913-7DOI Listing
January 2017

Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.

Diabetes 2016 Mar 2;65(3):803-17. Epub 2015 Dec 2.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.
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http://dx.doi.org/10.2337/db15-1313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764151PMC
March 2016

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Nat Genet 2015 Nov 28;47(11):1294-1303. Epub 2015 Sep 28.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
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http://dx.doi.org/10.1038/ng.3412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661791PMC
November 2015

Directional dominance on stature and cognition in diverse human populations.

Nature 2015 Jul 1;523(7561):459-462. Epub 2015 Jul 1.

Department of Nutrition and Dietetics, Harokopio University of Athens, 70, El. Venizelou Ave, Athens, 17671, Greece.

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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http://dx.doi.org/10.1038/nature14618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516141PMC
July 2015

A genetic risk score combining 32 SNPs is associated with body mass index and improves obesity prediction in people with major depressive disorder.

BMC Med 2015 Apr 17;13:86. Epub 2015 Apr 17.

MRC SGDP Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, Box PO82, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.

Background: Obesity is strongly associated with major depressive disorder (MDD) and various other diseases. Genome-wide association studies have identified multiple risk loci robustly associated with body mass index (BMI). In this study, we aimed to investigate whether a genetic risk score (GRS) combining multiple BMI risk loci might have utility in prediction of obesity in patients with MDD.

Methods: Linear and logistic regression models were conducted to predict BMI and obesity, respectively, in three independent large case-control studies of major depression (Radiant, GSK-Munich, PsyCoLaus). The analyses were first performed in the whole sample and then separately in depressed cases and controls. An unweighted GRS was calculated by summation of the number of risk alleles. A weighted GRS was calculated as the sum of risk alleles at each locus multiplied by their effect sizes. Receiver operating characteristic (ROC) analysis was used to compare the discriminatory ability of predictors of obesity.

Results: In the discovery phase, a total of 2,521 participants (1,895 depressed patients and 626 controls) were included from the Radiant study. Both unweighted and weighted GRS were highly associated with BMI (P < 0.001) but explained only a modest amount of variance. Adding 'traditional' risk factors to GRS significantly improved the predictive ability with the area under the curve (AUC) in the ROC analysis, increasing from 0.58 to 0.66 (95% CI, 0.62-0.68; χ(2) = 27.68; P < 0.0001). Although there was no formal evidence of interaction between depression status and GRS, there was further improvement in AUC in the ROC analysis when depression status was added to the model (AUC = 0.71; 95% CI, 0.68-0.73; χ(2) = 28.64; P <0.0001). We further found that the GRS accounted for more variance of BMI in depressed patients than in healthy controls. Again, GRS discriminated obesity better in depressed patients compared to healthy controls. We later replicated these analyses in two independent samples (GSK-Munich and PsyCoLaus) and found similar results.

Conclusions: A GRS proved to be a highly significant predictor of obesity in people with MDD but accounted for only modest amount of variance. Nevertheless, as more risk loci are identified, combining a GRS approach with information on non-genetic risk factors could become a useful strategy in identifying MDD patients at higher risk of developing obesity.
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http://dx.doi.org/10.1186/s12916-015-0334-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407390PMC
April 2015

Genome-wide association study of kidney function decline in individuals of European descent.

Kidney Int 2015 May 10;87(5):1017-29. Epub 2014 Dec 10.

Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia.

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.
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http://dx.doi.org/10.1038/ki.2014.361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425568PMC
May 2015

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Nature 2014 Oct 23;514(7520):92-97. Epub 2014 Jul 23.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" - Trieste, Italy.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
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http://dx.doi.org/10.1038/nature13545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185210PMC
October 2014

Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.

Am J Hum Genet 2014 Jul 19;95(1):24-38. Epub 2014 Jun 19.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.
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http://dx.doi.org/10.1016/j.ajhg.2014.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085636PMC
July 2014

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

PLoS Genet 2014 Feb 27;10(2):e1004123. Epub 2014 Feb 27.

Department of Endocrinology and Internal Medicine, University Hospital Ghent and Faculty of Medicine, Ghent University, Ghent, Belgium.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
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http://dx.doi.org/10.1371/journal.pgen.1004123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937134PMC
February 2014

Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.

J Am Soc Nephrol 2014 Aug 27;25(8):1869-82. Epub 2014 Feb 27.

Institute of Physiology, Zurich Center for Integrative Human Physiology, and Division of Nephrology, Catholic University of Louvain Medical School, Brussels, Belgium;

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.
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http://dx.doi.org/10.1681/ASN.2013070781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116060PMC
August 2014

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.

Hum Mol Genet 2014 May 19;23(9):2490-7. Epub 2013 Dec 19.

University of Exeter Medical School, Exeter, UK.

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.
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http://dx.doi.org/10.1093/hmg/ddt620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976329PMC
May 2014

Association of adiposity genetic variants with menarche timing in 92,105 women of European descent.

Am J Epidemiol 2013 Aug 4;178(3):451-60. Epub 2013 Apr 4.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, 137 East Franklin Street, Suite 306, Campus Box 8050, Chapel Hill, NC 27514-8050, USA.

Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
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http://dx.doi.org/10.1093/aje/kws473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816344PMC
August 2013

A genome-wide association study of early menopause and the combined impact of identified variants.

Hum Mol Genet 2013 Apr 9;22(7):1465-72. Epub 2013 Jan 9.

Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
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http://dx.doi.org/10.1093/hmg/dds551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596848PMC
April 2013

Genome-wide meta-analysis of common variant differences between men and women.

Hum Mol Genet 2012 Nov 27;21(21):4805-15. Epub 2012 Jul 27.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.
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http://dx.doi.org/10.1093/hmg/dds304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471397PMC
November 2012

Evidence of inbreeding depression on human height.

PLoS Genet 2012 19;8(7):e1002655. Epub 2012 Jul 19.

Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.
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http://dx.doi.org/10.1371/journal.pgen.1002655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400549PMC
January 2013
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