Background & Aims: Genetic factors associated with nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. Methods: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Results: Case-control analysis identified signals showing p values = F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated. Conclusions: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Lay summary: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individuals risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. ; Funding Agencies|EPoS (Elucidating Pathways of Steatohepatitis) consortium - Horizon 2020 Framework Program of the European Union [634413]; FLIP consortium(EuropeanUnion FP7 grant) [241762]; Newcastle NIHR Biomedical Research Centre
Meta-Analysis ; This is the final version of the article. Available from the American Diabetes Association via the DOI in this record. ; Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D. ; The major funding for this work comes from Council for Scientific and Industrial Research, Government of India, in the form of the grant "Diabetes mellitus—New drug discovery R&D, molecular mechanisms, and genetic and epidemiological factors" (NWP0032-19). R.T. received a postdoctoral fellowship from the Fogarty International Center and the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (D43-HD-065249).
Mieth, Bettina et al. ; The standard approach to the analysis of genome-wide association studies (GWAS) is based on testing each position in the genome individually for statistical significance of its association with the phenotype under investigation. To improve the analysis of GWAS, we propose a combination of machine learning and statistical testing that takes correlation structures within the set of SNPs under investigation in a mathematically well-controlled manner into account. The novel two-step algorithm, COMBI, first trains a support vector machine to determine a subset of candidate SNPs and then performs hypothesis tests for these SNPs together with an adequate threshold correction. Applying COMBI to data from a WTCCC study (2007) and measuring performance as replication by independent GWAS published within the 2008–2015 period, we show that our method outperforms ordinary raw p-value thresholding as well as other state-of-the-art methods. COMBI presents higher power and precision than the examined alternatives while yielding fewer false (i.e. non-replicated) and more true (i.e. replicated) discoveries when its results are validated on later GWAS studies. More than 80% of the discoveries made by COMBI upon WTCCC data have been validated by independent studies. Implementations of the COMBI method are available as a part of the GWASpi toolbox 2.0. ; EF acknowledges support from the advanced ERC grant (ERC-2011-AdG 295642-FEP) on the Foundation of Economic Preferences. MK, BM, and KRM were supported by the German National Science Foundation (DFG) under the grants MU 987/6-1 and RA 1894/1-1. TD and DS were supported by the German National Science Foundation (DFG) under the grants DI 1723/3-1 und SCHU 2828/2-1. GB and TS acknowledge support of the German National Science Foundation (DFG) under the research group grant FOR 1735. MK, DT, KRM, and GB acknowledge financial support by the FP7-ICT Programme of the European Community, under the PASCAL2 Network of Excellence. MK acknowledges a postdoctoral fellowship by the German Research Foundation (DFG), award KL 2698/2-1, and from the Federal Ministry of Science and Education (BMBF) awards 031L0023A and 031B0187B. AN acknowledges support from the Spanish Multiple Sclerosis Network (REEM), of the Instituto de Salud Carlos III (RD12/0032/0011), the Spanish National Institute for Bioinformatics (PT13/0001/0026) the Spanish Government Grant BFU2012-38236 and from FEDER. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 634143 (MedBioinformatics). MK and KRM were financially supported by the Ministry of Education, Science, and Technology, through the National Research Foundation of Korea under Grant R31-10008 (MK, KRM) and BK21 (KRM). ; Peer reviewed
Posttraumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We used genomewide association study (GWAS) and bioinformatic analyses, including 146,660 European-Americans (EAs) and 19,983 African-Americans (AAs) in the US Million Veteran Program, to identify genetic risk factors relevant to Intrusive reexperiencing of trauma -- the most characteristic symptom cluster of PTSD. In EAs, 8 distinct significant regions were identified. Three regions had P<5×10(−10) -- CAMKV; chromosome 17 closest to KANSL1 but within a large high-LD region that also includes CRHR1; and TCF4. Associations were enriched with respect to the transcriptomic profiles of striatal medium spiny neurons. No significant associations were observed in the AA part of the sample. Results in EAs were replicated in UK Biobank. These results provide new insights into the biology of PTSD in a well--powered GWAS.
In: 2018 , ' Long- and short-term outcomes in renal allografts with deceased donors : A large recipient and donor genome-wide association study ' , American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons . https://doi.org/10.1111/ajt.14594
Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.
Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass. ; NIH [N01 AG 12100, U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, U01 HL084756, N01-AG-12100, U24AG051129]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Mid-Atlantic Nutrition and Obesity Research Center of Maryland [P30 DK072488]; NIH/NIAMS [F32AR059469]; American Heart Association [10SDG2690004]; NHLBI [N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, HL080295, HL087652, HL105756, HL103612, HL120393, HL130114]; NINDS; NIA [AG-023629, AG-15928, AG-20098, AG-027058, 1R01AG032098-01A1]; National Center for Research Resources [UL1RR033176]; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease grant [DK063491]; Southern California Diabetes Endocrinology Research Center; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Swiss National Science Foundation [33CSCO-122661, 33CS30-139468, 33CS30-148401]; deCODE Genetics, ehf; Cancer Research United Kingdom; Medical Research Council; EU [LSHM-CT-2003-503041]; Wellcome Trust [WT098051, WT089062, WT098017]; Netherlands Organisation for Scientific Research (NWO); Erasmus MC; Centre for Medical Systems Biology (CMSB); European Community's Seventh Framework Programme (FP7), ENGAGE Consortium [HEALTH-F4-2007-201413]; Wellcome Trust; Support for Science Funding programme; CamStrad; Danish Council for Independent Research [DFF-1333-00124, DFF-1331-00730B]; US National Institute for Arthritis, Musculoskeletal and Skin Diseases; National Institute on Aging [U24AG051129, R01 AR 41398, R01AR057118]; FP7-PEOPLE-Marie Curie Career Integration Grants (CIG); National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; Genome Quebec; Genome Canada; Canadian Institutes of Health Research (CIHR); Swedish Research Council; Swedish Foundation for Strategic Research; ALF/LUA research grant in Gothenburg; Lundberg Foundation; Emil and Vera Cornell Foundation; Torsten and Ragnar Soderberg's Foundation; Petrus and Augusta Hedlunds Foundation; Vastra Gotaland Foundation; Goteborg Medical Society; German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015G]; National Institutes of Aging; National Institutes of Health [HHSN268200782096C, R01 AG 041517, M01 RR-00750]; Intramural Research Program of the NIH, National Library of Medicine. Kora; Helmholtz Center Munich, German Research Center for Environmental Health; German Federal Ministry of Education and Research (BMBF); State of Bavaria; German National Genome Research Network [NGFN-2, NGFNPlus: 01GS0823]; Munich Center of Health Sciences (MC Health) as part of LMUinnovativ; British Heart Foundation; Kidney Research UK; National Institute for Health Research (NIHR) programme grant; Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; National Institute on Aging grants [R01AG17917, R01AG15819, R01AG24480]; Illinois Department of Public Health; Rush Clinical Translational Science Consortium; Arthritis Research UK; Chronic Disease Research Foundation; National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award; Israel Science Foundation [994/10]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); German Federal Ministry of Education and Research (BMBF) [16SV5536K, 16SV5537, 16SV5538, 16SV5837, 01UW0808]; Max Planck Institute for Human Development (MPIB); Max Planck Institute for Molecular Genetics (MPIMG); Charite University Medicine; German Institute for Economic Research (DIW); University of Lubeck in Lubeck, Germany; Netherlands Organization for Health Research and Development (ZonMw) the Hague [6130.0031]; NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation, the Hague [KB-15-004-003]; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam; Healthway Health Promotion Foundation of Western Australia; Australasian Menopause Society; Australian National Health and Medical Research Council [254627, 303169, 572604]; National Health and Medical Research Council of Australia Career Development Fellowship; Karen Elise Jensen foundation; NIH from NHLBI [R01-HL-117078, R01-HL-087700, R01-HL-088215]; NIH from NIDDK [R01-DK-089256, R01-DK-075681]; Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]; Academy of Finland [251217, 136895, 141005, 139635, 129494, 269517]; Finnish foundation for Cardiovascular Research; Sigrid Juselius Foundation; Yrjo Jahnsson Foundation; Finnish Diabetes Research Society; Samfundet Folkhalsann; Novo Nordisk Foundation; Liv och Halsa; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Centers for Disease Control and Prevention/Association of Schools of Public Health [S043, S1734, S3486]; NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant [5-P60-AR30701]; NIAMS Multidisciplinary Clinical Research Center grant [5 P60 AR49465-03]; Research Program - Korea Centers for Disease Control and Prevention [2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00]; Helmholtz Center Munich; German Research Center for Environmental Health; British Heart Foundation Grant [SP/04/002]; Academy of Finland; Finnish Diabetes Research Foundation; Finnish Cardiovascular Research Foundation; Strategic Research Funding from the University of Eastern Finland, Kuopio; EVO grant from the Kuopio University Hospital [5263]; Swedish Research Council [2006-3832, K2009-53X-14691-07-3, K2010-77PK-21362-01-2, 2008-2202, 2005-8214]; Greta and Johan Kock Foundation; A. Pahlsson Foundation; A. Osterlund Foundation; Malmo University Hospital Research Foundation; Research and Development Council of Region Skane, Sweden; Swedish Medical Society; National Institutes of Health; National Institute on Aging (NIA); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, UL1 TR000128]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [RC2ARO58973]; FAS [2007-2125]; Chief Scientist Office of the Scottish Government [CZB/4/276, CZB/4/710]; Royal Society; MRC Human Genetics Unit; Arthritis Research UK [17539]; European Union framework program 6 EUROSPAN project [LSHG-CT-2006-018947]; ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden; European Union Grant [QLG1-CT-2001-01252]; AstraZeneca; SHIP, part of the Community Medicine Research Network of the University of Greifswald, Germany; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; network "Greifswald Approach to Individualized Medicine (GANI_MED)" - Federal Ministry of Education and Research [03IS2061A]; Siemens Healthcare, Erlangen, Germany; National Institute on Aging (NIA) [R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576]; Wallenberg foundation; Medical Research Council (UK); Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; US National Institutes of Health grants [1-ZIA-HG000024, U01DK062370, R00DK099240]; American Diabetes Association Pathway to Stop Diabetes Grant [1-14-INI-07]; Academy of Finland Grants [271961, 272741, 258753]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA; National Heart Lung and Blood Institute of the National Institutes of Health [HL57453]; [HHSN268201200036C] ; This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. 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Feed efficiency (FE) is one of the most economically and environmentally relevant traits in the animal production sector. The objective of this study was to gain knowledge about the genetic control of FE in rabbits. To this end, GWASs were conducted for individual growth under two feeding regimes (full feeding and restricted) and FE traits collected from cage groups, using 114 604 autosome SNPs segregating in 438 rabbits. Two different models were implemented: (1) an animal model with a linear regression on each SNP allele for growth trait; and (2) a two‐trait animal model, jointly fitting the performance trait and each SNP allele content, for FE traits. This last modeling strategy is a new tool applied to GWAS and allows information to be considered from non‐genotyped individuals whose contribution is relevant in the group average traits. A total of 189 SNPs in 17 chromosomal regions were declared to be significantly associated with any of the five analyzed traits at a chromosome‐wide level. In 12 of these regions, 20 candidate genes were proposed to explain the variation of the analyzed traits, including genes such as FTO, NDUFAF6 and CEBPA previously associated with growth and FE traits in monogastric species. Candidate genes associated with behavioral patterns were also identified. Overall, our results can be considered as the foundation for future functional research to unravel the actual causal mutations regulating growth and FE in rabbits. ; This study was financed by Feed‐a‐Gene, which has received funding from the European Union's H2020 program under grant agreement no. 63353 and the Spanish projects RTA2014‐00015‐C2‐01, RTA2011‐00064‐00‐00 and RTI2018‐097610‐R‐I00. M. Ballester is financially supported by a Ramon y Cajal contract (RYC‐2013‐12573) from the Spanish Ministry of Economy and Competitiveness. ; Peer reviewed
Funding: We acknowledge support from the US National Institutes of Health (http://www.nih.gov/) (grant 2R01GM078536 and 2P4ES007373-19A1 to DES), European Commission (http://ec.europa.eu/index_en.htm) (grant PCIG9-GA-2011-291798 to DES) and UK Biotechnology and Biological Sciences Research Council (http://www.bbsrc.ac.uk/home/home.aspx) (grants BB/L000113/1 to DES, and BB/H006303/1 to FJZ) and the Ministry of Education of China (http://www.moe.edu.cn/publicfiles/business/htmlfiles/moe/moe_2792/) (grant IRT1256 to FJZ), start-up funds from the Shanghai Institutes for Biological Sciences (http://english.sibs.cas.cn/) to DYC, the '1000 youth talents program' from the Chinese Central Government (http://www.1000plan.org/) to DYC, and the Diamond Light Source (http://www.diamond.ac.uk/Home.html) for the provision of synchrotron beamtime (grant SP9505 to FJZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Peer reviewed ; Publisher PDF
Genome-wide association studies (GWAS) are a common approach for systematic discovery of single nucleotide polymorphisms (SNPs) which are associated with a given disease. Univariate analysis approaches commonly employed may miss important SNP associations that only appear through multivariate analysis in complex diseases. However, multivariate SNP analysis is currently limited by its inherent computational complexity. In this work, we present a computational framework that harnesses supercomputers. Based on our results, we estimate a three-way interaction analysis on 1.1 million SNP GWAS data requiring over 5.8 years on the full "Avoca" IBM Blue Gene/Q installation at the Victorian Life Sciences Computation Initiative. This is hundreds of times faster than estimates for other CPU based methods and four times faster than runtimes estimated for GPU methods, indicating how the improvement in the level of hardware applied to interaction analysis may alter the types of analysis that can be performed. Furthermore, the same analysis would take under 3 months on the currently largest IBM Blue Gene/Q supercomputer "Sequoia" at the Lawrence Livermore National Laboratory assuming linear scaling is maintained as our results suggest. Given that the implementation used in this study can be further optimised, this runtime means it is becoming feasible to carry out exhaustive analysis of higher order interaction studies on large modern GWAS. ; This research was partially funded by NHMRC grant 1033452 and was supported by a Victorian Life Sciences Computation Initiative (VLSCI) grant number 0126 on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia.
Genome-wide association studies and biobanks are at the forefront of genomics research and possess unprecedented potential to improve public health. However, for public health genomics to ultimately fulfill its potential, technological and scientific advances alone are insufficient. Scientists, ethicists, policy makers, and regulators must work closely together with research participants and communities in order to craft an equitable and just ethical framework, and a sustainable environment for effective policies. Such a framework should be a 'hybrid' form which balances equity and solidarity with entrepreneurship and scientific advances. A good balance between research and policy on one hand, and privacy, protection and trust on the other is the key for public health improvement based on advances in genomics science.
Funding: AG and TFMA were supported by the Munich Cluster for Systems Neurology (SyNergy). AG 535 was supported by Fondazione Umberto Veronesi. SP is a Royal Society University Research fellow. BMM, CF, BSP and SEF are supported by the Max Planck Society. AW, BM and HK were funded by the Fraunhofer Society and the Max Planck Society within the 'Pakt für Forschung und Innovation'. HK was also supported by LIFE – Leipzig Research Center for Civilization Diseases funded by means of the European Union; the European Regional Development Fund (ERDF); and the Free State of Saxony within the excellence initiative. FR is supported by Agence Nationale de la Recherche (ANR-06-NEURO-019-01, ANR-17-EURE-542 0017 IEC, ANR-10-IDEX-0001-02 PSL, ANR-11-BSV4-014-01), European Commission (LSHM-CT-2005-018696). TFMA was supported by the BMBF through the DIFUTURE consortium of the Medical Informatics Initiative Germany (grant 01ZZ1804A) and by the European Union's Horizon 2020 Research and Innovation Programme (grant MultipleMS, EU RIA 733161). ; Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence. ; Publisher PDF ; Peer reviewed
Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association ($P$-value≤5×10$^{−8}$) in 20 variants located at the $\textit{CFH}$ gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR)=0.62, 95% confidence interval (C.I.)=0.52–0.73; $P$-value=9.62×10$^{−9}$). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR=0.64, 95% C.I.)=0.55–0.76, $\textit{P-value}$=3.25×10$^{−8}$). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of $\textit{CFH}$ with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease. ; This study received support from the Instituto de Salud Carlos III (Proyecto de Investigación en Salud, Acción Estratégica en Salud: proyecto GePEM PI16/01478) (A.S.); Instituto Carlos III (Intensificación de la actividad investigadora) (A.V.); Consellería de Sanidade, Xunta de Galicia (RHI07/2-intensificación actividad investigadora, PS09749 and 10PXIB918184PR), Instituto de Salud Carlos III (Intensificación de la actividad investigadora 2007–2012, PI16/01569), Convenio de colaboración de investigación (Wyeth España-Fundación IDICHUS 2007–2011), Convenio de colaboración de investigación (Novartis España-Fundación IDICHUS 2010–2011), Fondo de Investigación Sanitaria (FIS; PI070069/PI1000540) del plan nacional de I+ D+ I and 'fondos FEDER' (F.M.T.). More information at: www. esigem.org. The UK cohort was established with support of the Meningitis Research Foundation (UK), who provide ongoing support, and the European Society for Paediatric Infectious Diseases supported the establishment of the international collaboration. This study makes use of data generated by the Wellcome Trust Case-Control Consortium 2. A full list of the investigators who contributed to the generation of the data is available from www. wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 085475. The research leading to these results has received funding from the European Union's Seventh Framework Programme under EC-GA No. 279185 (EUCLIDS).
This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- CIMBA et al. ; BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. ; The study was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defense Ovarian Cancer Idea award (W81XWH-10-1-0341), grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure; Cancer Research UK grants C12292/A11174 and C1287/A10118; the European Commission's Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175). Breast Cancer Family Registry Studies (BCFR): supported by the National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), and University of Melbourne (U01 CA69638). The Australian BCFR was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. Melissa C. Southey is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. Carriers at FCCC were also identified with support from National Institutes of Health grants P01 CA16094 and R01 CA22435. The New York BCFR was also supported by National Institutes of Health grants P30 CA13696 and P30 ES009089. The Utah BCFR was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1 RR025764, and by Award Number P30 CA042014 from the National Cancer Institute. Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): BFBOCC is partly supported by Lithuania (BFBOCC-LT), Research Council of Lithuania grant LIG-19/2010, and Hereditary Cancer Association (Paveldimo vėžio asociacija). ; Latvia (BFBOCC-LV) is partly supported by LSC grant 10.0010.08 and in part by a grant from the ESF Nr.2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016.BRCA-gene mutations and breast cancer in South African women (BMBSA): BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. Beckman Research Institute of the City of Hope (BRICOH): Susan L. Neuhausen was partially supported by the Morris and Horowitz Families Endowed Professorship. BRICOH was supported by NIH R01CA74415 and NIH P30 CA033752. Copenhagen Breast Cancer Study (CBCS): The CBCS study was supported by the NEYE Foundation. Spanish National Cancer Centre (CNIO): This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. City of Hope Cancer Center (COH): The City of Hope Clinical Cancer Genetics Community Research Network is supported by Award Number RC4A153828 (PI: Jeffrey N. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): CONSIT TEAM was funded by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project "Hereditary tumors"), Italian Association for Cancer Research (AIRC, IG 8713), Italian Minitry of Health (Extraordinary National Cancer Program 2006, "Alleanza contro il Cancro" and "Progetto Tumori Femminili), Italian Ministry of Education, University and Research (Prin 2008) Centro di Ascolto Donne Operate al Seno (CAOS) association and by funds from Italian citizens who allocated the 5×1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5×1000'). German Cancer Research Center (DKFZ): The DKFZ study was supported by the DKFZ. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the NWO grant 91109024, the Pink Ribbon grant 110005, and the BBMRI grant CP46/NWO. ; Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Rosalind A. Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Fox Chase Cancer Canter (FCCC): The authors acknowledge support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. Andrew K. Godwin was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): The GEMO study was supported by the Ligue National Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award and the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program. Gynecologic Oncology Group (GOG): This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), Statistical and Data Center (CA 37517), and GOG's Cancer Prevention and Control Committtee (CA 101165). Drs. Mark H. Greene and Phuong L. Mai were supported by funding from the Intramural Research Program, NCI, NIH. Hospital Clinico San Carlos (HCSC): HCSC was supported by RETICC 06/0020/0021, FIS research grant 09/00859, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitivity, and the European Regional Development Fund (ERDF). ; Helsinki Breast Cancer Study (HEBCS): The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. Molecular Genetic Studies of Breast and Ovarian Cancer in Hungary (HUNBOCS): HUNBOCS was supported by Hungarian Research Grant KTIA-OTKA CK-80745 and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/ÖP-9. Institut Català d'Oncologia (ICO): The ICO study was supported by the Asociación Española Contra el Cáncer, Spanish Health Research Foundation, Ramón Areces Foundation, Carlos III Health Institute, Catalan Health Institute, and Autonomous Government of Catalonia and contract grant numbers: ISCIIIRETIC RD06/0020/1051, PI09/02483, PI10/01422, PI10/00748, 2009SGR290, and 2009SGR283. International Hereditary Cancer Centre (IHCC): Supported by the Polish Foundation of Science. Katarzyna Jaworska is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. Iceland Landspitali–University Hospital (ILUH): The ILUH group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): INHERIT work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program, the Canadian Breast Cancer Research Alliance grant 019511 and the Ministry of Economic Development, Innovation and Export Trade grant PSR-SIIRI-701. Jacques Simard is Chairholder of the Canada Research Chair in Oncogenetics. ; Istituto Oncologico Veneto (IOVHBOCS): The IOVHBOCS study was supported by Ministero dell'Istruzione, dell'Università e della Ricerca and Ministero della Salute ("Progetto Tumori Femminili" and RFPS 2006-5-341353,ACC2/R6.9"). Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): kConFab is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. Amanda B. Spurdle is an NHMRC Senior Research Fellow. The Clinical Follow Up Study was funded from 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333. Mayo Clinic (MAYO): MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. McGill University (MCGILL): The McGill Study was supported by Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation, and Export Trade. Memorial Sloan-Kettering Cancer Center (MSKCC): The MSKCC study was supported by Breast Cancer Research Foundation, Niehaus Clinical Cancer Genetics Initiative, Andrew Sabin Family Foundation, and Lymphoma Foundation. Modifier Study of Quantitative Effects on Disease (MODSQUAD): MODSQUAD was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Women's College Research Institute, Toronto (NAROD): NAROD was supported by NIH grant: 1R01 CA149429-01. National Cancer Institute (NCI): Drs. Mark H. Greene and Phuong L. Mai were supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Rockville, MD. National Israeli Cancer Control Center (NICCC): NICCC is supported by Clalit Health Services in Israel. Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N. N. Petrov Institute of Oncology (NNPIO): The NNPIO study has been supported by the Russian Foundation for Basic Research (grants 11-04-00227, 12-04-00928, and 12-04-01490), the Federal Agency for Science and Innovations, Russia (contract 02.740.11.0780), and through a Royal Society International Joint grant (JP090615). The Ohio State University Comprehensive Cancer Center (OSU-CCG): OSUCCG is supported by the Ohio State University Comprehensive Cancer Center. ; South East Asian Breast Cancer Association Study (SEABASS): SEABASS is supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): The SMC study was partially funded through a grant by the Israel Cancer Association and the funding for the Israeli Inherited Breast Cancer Consortium. Swedish Breast Cancer Study (SWE-BRCA): SWE-BRCA collaborators are supported by the Swedish Cancer Society. The University of Chicago Center for Clinical Cancer Genetics and Global Health (UCHICAGO): UCHICAGO is supported by grants from the US National Cancer Institute (NIH/NCI) and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. University of California Los Angeles (UCLA): The UCLA study was supported by the Jonsson Comprehensive Cancer Center Foundation and the Breast Cancer Research Foundation. University of California San Francisco (UCSF): The UCSF study was supported by the UCSF Cancer Risk Program and the Helen Diller Family Comprehensive Cancer Center. United Kingdom Familial Ovarian Cancer Registries (UKFOCR): UKFOCR was supported by a project grant from CRUK to Paul Pharoah. University of Pennsylvania (UPENN): The UPENN study was supported by the National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855), Breast Cancer Research Foundation, Rooney Family Foundation, Susan G. Komen Foundation for the Cure, and the Macdonald Family Foundation. Victorian Familial Cancer Trials Group (VFCTG): The VFCTG study was supported by the Victorian Cancer Agency, Cancer Australia, and National Breast Cancer Foundation. Women's Cancer Research Initiative (WCRI): The WCRI at the Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). ; Peer Reviewed
peer-reviewed ; H.D.D., A.J.C., P.J.B. and B.J.H. would like to acknowledge the Dairy Futures Cooperative Research Centre for funding. H.P. and R.F. acknowledge funding from the German Federal Ministry of Education and Research (BMBF) within the AgroClustEr 'Synbreed—Synergistic Plant and Animal Breeding' (grant 0315527B). H.P., R.F., R.E. and K.-U.G. acknowledge the Arbeitsgemeinschaft Süddeutscher Rinderzüchter, the Arbeitsgemeinschaft Österreichischer Fleckviehzüchter and ZuchtData EDV Dienstleistungen for providing genotype data. A. Bagnato acknowledges the European Union (EU) Collaborative Project LowInputBreeds (grant agreement 222623) for providing Brown Swiss genotypes. Braunvieh Schweiz is acknowledged for providing Brown Swiss phenotypes. H.P. and R.F. acknowledge the German Holstein Association (DHV) and the Confederación de Asociaciones de Frisona Española (CONCAFE) for sharing genotype data. H.P. was financially supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (DFG) (grant PA 2789/1-1). D.B. and D.C.P. acknowledge funding from the Research Stimulus Fund (11/S/112) and Science Foundation Ireland (14/IA/2576). M.S. and F.S.S. acknowledge the Canadian Dairy Network (CDN) for providing the Holstein genotypes. P.S. acknowledges funding from the Genome Canada project entitled 'Whole Genome Selection through Genome Wide Imputation in Beef Cattle' and acknowledges WestGrid and Compute/Calcul Canada for providing computing resources. J.F.T. was supported by the National Institute of Food and Agriculture, US Department of Agriculture, under awards 2013-68004-20364 and 2015-67015-23183. A. Bagnato, F.P., M.D. and J.W. acknowledge EU Collaborative Project Quantomics (grant 516 agreement 222664) for providing Brown Swiss and Finnish Ayrshire sequences and genotypes. A.C.B. and R.F.V. acknowledge funding from the public–private partnership 'Breed4Food' (code BO-22.04-011- 001-ASG-LR) and EU FP7 IRSES SEQSEL (grant 317697). A.C.B. and R.F.V. acknowledge CRV (Arnhem, the Netherlands) for providing data on Dutch and New Zealand Holstein and Jersey bulls. ; Stature is affected by many polymorphisms of small effect in humans1. In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P < 5 × 10−8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP–seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals.