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Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.<\/ns5:p>","DOI":"10.12688\/wellcomeopenres.18754.1","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T11:20:24Z","timestamp":1697800824000},"page":"483","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization"],"prefix":"10.12688","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6803-3007","authenticated-orcid":false,"given":"Sara M.","family":"Willems","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha H. 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Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-483\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-483\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-483\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T08:00:17Z","timestamp":1727683217000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-483\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,20]]},"references-count":48,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.18754.1","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.20795.r69837","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.20795.r96202","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.20795.r69837","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.20795.r96202","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,20]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-483\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.20795.r69837, Toshimasa Yamauchi, Department of Diabetes and Metabolic Diseases, University of Tokyo Graduate School of Medicine, Tokyo, 22 Jan 2024, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-483\/v1#referee-response-69837","order":0,"name":"referee-response-69837","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.20795.r96202, Eiji Kutoh, Gyoda General Hospital, Saitama, 13 Sep 2024, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-483\/v1#referee-response-96202","order":1,"name":"referee-response-96202","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Sara Willems<\/b>; \n<i>Posted: 27 Sep 2024<\/i>; We would like to thank Dr. Kutoh very much for his time and effort! Below our answers to the points raised: &nbsp;  - Our aim here was to generate exome array summary statistics resources to help effector gene prioritization for further (also other than in silico) research. Historically, large-scale meta-analyses results such as those we have shared here have stood the test of time and findings have been widely reproducible,&nbsp; In addition, by making our results publicly available we are ensuring that others can use the data and test their reproducibility. &nbsp;  - Since up to 66 cohorts where included in the meta-analyses presented in our study, many people have substantially contributed to collecting and analysing individual cohort data. More details of the contributions can be found under the tab &acute;Authors&acute;. &nbsp;  - In this study, we only asked the contributing cohorts to exclude individuals with diagnosed or treated diabetes from the analyses. We did this to exclude any consequence of diabetes treatments or related interventions on the quantitative gycaemic traits that we analysed. To controll for confounding by BMI, all analyses were adjusted for BMI. We have previously demonstrated that collider bias did not significantly affect results with BMI adjustment (Chen J, Spracklen CN, Marenne G, et al.: The trans-ancestral genomic architecture of glycemic traits. Nat Genet. 2021; 53(6): 840\u2013860). Furthermore, gene discovery studies on glycaemic traits using the same inclusion \/ exclusion criteria and covariates as we did have proven valuable in discovering loci influencing glycaemic traits, a subset of which also influence risk of type 2 diabetes.&nbsp; &nbsp;  - We asked all cohorts with the required data that we knew of at the time of this study to participate. We agree with the reviewer that this study still has over-representation of participants of recent European ancestry. Unfortunately this is a well recognised problem in the broader field of human genetics, and one we tried to mitigate by reaching out to studies that had data from participants on non-European ancestry. Because of different allele frequencies in different ancestries, statistical power for detection of associations can indeed be different in different ancestries. For more on this topic and the value of multiple ancestry analyses, please see our study Chen J, Spracklen CN, Marenne G,&nbsp;\n<i>et al.<\/i>: The trans-ancestral genomic architecture of glycemic traits.&nbsp;\n<i>Nat Genet.<\/i>&nbsp;2021;&nbsp;\n<b>53<\/b>(6): 840\u2013860.&nbsp; &nbsp;  - At the time of the study, this technology (exome array) was significantly cheaper and easier to implement than whole-exome sequencing, which also made it possible to implement in studies that did not have the resources to undertake whole-exome sequencing. We found it really worthwhile to analyse these data, since it contains a very interesting collection of variants (see our Methods section). &nbsp;  - We asked all cohorts to provide information on their collection method, assay and sample and for insulin additionally the assay sensitivity (see Supplementary Table S1). We asked cohorts to use plasma values for the analyses. If glucose measurement was made in blood, values were adjusted multiplying by 1.13, since plasma values are about 10-15% higher than blood values. &nbsp;  - This (500 kb) is a common threshold in genetic association studies, since variants that are closer together are very likely to be in high LD and thus to represent the same genetic locus. To make sure we didn&acute;t miss distinct variant associations that are closer together at novel loci, we used Raremetal v 4.12.8 to perform analyses conditioning on the most significant variant at the locus and then looked for other significantly associated variants at that locus. These analyses were repeated by including the next most significant and distinct associated variant until no exome- or genome-wide significantly-associated variants were left at the locus. Additionally, gene-based analyses were performed aggregating all variants fullfilling mask criteria (see our Methods section). This was done for all genes with at least 2 variants fulfilling these criteria. &nbsp;  - Our main aim here was to generate exome array summary statistics resources to help effector gene prioritization for further (also other than in silico) research. However, to gain further biological insights, we also used the summary statistics to perform pathway analyses. These identified pathways related to processes like insulin secretion, zinc transport, fatty acid metabolism and, for HbA1c associations, a strong enrichment in pathways related to blood cell biology (for more details on these results, please see our results section).&nbsp; Apart from gaining insight into the biology underlying each glycemic trait, these analyses may further help the prioritization of specific genes or pathways for further research on these important questions raised by the reviewer on clinical interpretations and implications of our results. &nbsp; -The reviewer raises the point &acute;The exclusion of individuals with diabetes is mentioned, but the rationale could be elaborated upon. Could this exclusion introduce bias? Does it ensure that the identified associations are specific to glycemic traits in non-diabetic individuals?&acute;. Here we refer to the answer regarding biases above, which also includes this point. &nbsp; - In GWAS analyses (mainly identifying common non-coding variant associations), replication studies have often been performed to additionally control for false positives. To increase power (also to detect potential rarer coding variant associations), we choose to make our discovery cohort as large as possible. In addition, historically, as mentioned above, large-scale meta-analyses results such as those we have shared here have stood the test of time and findings have been widely reproducible.&nbsp; And by making our results publicly available we are ensuring that others can use the data and test their reproducibility. &nbsp;  - We feel we sufficiently acknowledge the influence of red blood cell biology on HbA1c levels&nbsp; and don&acute;t base conclusions about glycemic control solely on HbA1c analyses. For example in the pathway analyses, we describe the strong enrichment for blood-related pathways mainly driven by HbA1c-associated variants and, to disentangle blood cell turnover from effects due to glycation, repeated analyses excluding variants that were significantly associated with HbA1c only. Also regarding SV2C, we describe it&acute;s associations with red blood cell traits and lack of association with other glycemic traits, suggesting its effect on HbA1c is independent of glycemia.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-483\/v1#referee-comment-5826","order":2,"name":"referee-comment-5826","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by Wellcome [grant numbers 095101 and 200837 to Anna Gloyn]; In\u00eas Barroso is funded by Wellcome (WT206194) and this work was partly supported by \u201cExpanding excellence in England\u201d award from Research England; The Fenland Study is funded by Wellcome Trust and the Medical Research Council (MC_U106179471); Genotyping of the Generation Scotland GS:SFHS samples was funded by the Wellcome Trust (Wellcome Trust Strategic Award \u201cSTratifying Resilience and Depression Longitudinally\u201d (STRADL) Reference 104036\/Z\/14\/Z) and the Medical Research Council UK. Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD\/16\/6 and the Scottish Funding Council HR03006; GoDARTS study was funded by The Wellcome Trust Study Cohort Wellcome Trust Functional Genomics Grant (2004-2008) (Grant No: 072960\/2\/03\/2) and The Wellcome Trust Scottish Health Informatics Programme (SHIP) (2009-2012). (Grant No: 086113\/Z\/08\/Z); For HELIC MANOLIS and HELIC Pomak this work was funded by the Wellcome Trust (098051) and the European Research Council (ERC-2011-StG 280559-SEPI); The LOLIPOP study is supported by the Wellcome Trust (084723\/Z\/08\/Z), the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP\/04\/002), the Medical Research Council (G0601966,G0700931), the NIHR (RP-PG-0407-10371), European Union FP7 (EpiMigrant, 279143) and Action on Hearing Loss (G51). Mark I McCarthy was funded by Wellcome (grant numbers 090532, 098381, 106130, 203141 and 212259) and NIH U01-DK105535; Genotyping and analysis of PIVUS and ULSAM were funded by the Wellcome Trust under awards WT064890, WT090532 and WT098017. PIVUS and ULSAM are supported by the Swedish Research Council, Swedish Heart-Lung Foundation, Swedish Diabetes Foundation and Uppsala University; TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy\u2019s and St Thomas\u2019 NHS Foundation Trust in partnership with King\u2019s College London; 1958 British Birth cohort: analysis was supported by BHF programme grant (Deloukas) RG\/14\/5\/30893; AGES has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament); The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding support for \u201cBuilding on GWAS for NHLBI-diseases: the U.S. CHARGE consortium\u201d was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). ML was supported by a National Heart, Lung, and Blood Institute T32-HL0072024 Cardiovascular Epidemiology Training Grant; ASCOT: this work was supported by Pfizer, New York, NY, USA, for the ASCOT study and the collection of the ASCOT DNA repository, by Servier Research Group, Paris, France and by Leo Laboratories, Copenhagen, Denmark; Athero-Express Biobank Study: Dr. Sander W. van der Laan is funded through EU H2020 TO_AITION (grant number: 848146). We are thankful for the support of the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011\/B019 and CVON 2017-20: Generating the best evidence-based pharmaceutical targets for atherosclerosis [GENIUS I&II]), the ERA-CVD program \u2018druggable-MI-targets\u2019 (grant number: 01KL1802), and the Leducq Fondation \u2018PlaqOmics\u2019; BioMe: The Mount Sinai BioMe Biobank is supported by The Andrea and Charles Bronfman Philanthropies; Caroline Hayward is supported by an MRC University Unit Programme Grant \u201cQTL in Health and Disease\u201d (U. MC_UU_00007\/10); CHS: this CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086 and 75N92021D00006; and NHLBI grants U01HL080295, R01HL068986, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center; COPSAC2000: We greatly acknowledge the private and public research funding allocated to COPSAC and listed on www.copsac.com, with special thanks to The Lundbeck Foundation (Grant nr. R16-A1694), Ministry of Health (Grant nr. 903516), Danish Council for Strategic Research (Grant nr.: 0603-00280B), The Danish Council for Independent Research and The Capital Region Research Foundation as core supporters; CROATIA_Korcula: Exome array genotyping was funded by UK\u2019s Medical Research Council; DIABNORD: the current study was funded by Novo Nordisk, the Swedish Research Council, P\u00e5hlssons Foundation, the Swedish Heart Lung Foundation, and the Sk\u00e5ne Regional Health Authority (all to PWF); The DPS has been financially supported by grants from the Academy of Finland (117844 and 40758, 211497, and 118590 (MU); The EVO funding of the Kuopio University Hospital from Ministry of Health and Social Affairs (5254), Finnish Funding Agency for Technology and Innovation (40058\/07), Nordic Centre of Excellence on \u2018Systems biology in controlled dietary interventions and cohort studies, SYSDIET (070014), The Finnish Diabetes Research Foundation, Yrj\u00f6 Jahnsson Foundation (56358), Sigrid Juselius Foundation and TEKES grants 70103\/06 and 40058\/07; The DR's EXTRA Study was supported by the Ministry of Education and Culture of Finland (722 and 627;2004-2011), Academy of Finland (102318; 104943;123885; 211119), Kuopio University Hospital, Finnish Diabetes Association, Finnish Foundations for Cardiovascular Research, P\u00e4ivikki and Sakari Sohlberg Foundation, by European Commission FP6 Integrated Project (EXGENESIS); LSHM-CT-2004-005272, City of Kuopio and Social Insurance Institution of Finland (4\/26\/2010); EFSOCH: this paper presents independent research supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility; The EPIC-Norfolk study (DOI 10.22025\/2019.10.105.00004) has received funding from the Medical Research Council (MR\/N003284\/1 and MC-UU_12015\/1) and Cancer Research UK (C864\/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048); EPIC-Potsdam: the study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) and the State of Brandenburg to the German Center for Diabetes Research (DZD e.V.) (82DZD00302). The recruitment phase of the EPIC-Potsdam study was supported by the Federal Ministry of Science, Germany (01 EA 9401) and the European Union (SOC 95201408 05 F02). The follow-up of the EPIC-Potsdam study was supported by German Cancer Aid (70-2488-Ha I) and the European Community (SOC 98200769 05 F02); EpiHealth was supported by the Swedish Research Council strategic research network Epidemiology for Health, Uppsala University and Lund University. Genotyping in EpiHealth was supported by Swedish Heart-Lung Foundation (grant no. 20120197 and 20140422), Knut och Alice Wallenberg Foundation (grant no. 2013.0126), and Swedish Research Council (grant no. 2012-1397); Erasmus Rucphen Family (ERF) was supported by the Consortium for Systems Biology (NCSB), both within the framework of the Netherlands Genomics Initiative (NGI)\/Netherlands Organisation for Scientific Research (NWO). ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7\/2007-2013)\/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme \u201cQuality of Life and Management of the Living Resources\u201d of 5th Framework Programme (no. QLG2-CT-2002-01254) as well as FP7 project EUROHEADPAIN (nr 602633). High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043).The exome-chip measurements have been funded by the Netherlands Organization for Scientific Research (NWO; project number 184021007) and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl (http:\/\/www.bbmri.nl) ). Ayse Demirkan is supported by a Veni grant (2015) from ZonMw. Ayse Demirkan, Jun Liu and Cornelia van Duijn have used exchange grants from PRECEDI; The Family Heart Study (FamHS) was supported by NIH grants R01-HL-087700 and R01-HL-088215 from NHLBI, and R01-DK-8925601 and R01-DK-075681 from NIDDK; The FIA3 study was supported in part by a grant from the Swedish Heart-Lund Foundation (to PWF); The FIN-D2D 2007 study was supported by funds from the hospital districts of Pirkanmaa; Southern Ostrobothnia; North Ostrobothnia; Central Finland and Northern Savo; the Finnish National Public Health Institute; the Finnish Diabetes Association; the Ministry of Social Affairs and Health in Finland; Finland\u2019s Slottery Machine Association; the Academy of Finland [grant number 129293] and Commission of the European Communities, Directorate C-Public Health [grant agreement no. 2004310]; FINRISK 2007: VS was supported by the Finnish Foundation for Cardiovascular Research. PJ was supported by the Academy of Finland #118065; Folkert Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre; Framingham Heart Study: Genotyping, quality control and calling of the Illumina HumanExome BeadChip in the Framingham Heart Study was supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research (Daniel Levy and Christopher J. O\u2019Donnell, Principle Investigators).  Also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) U01 DK078616, UM1 DK078616, NIDDK K24 DK080140 and American Diabetes Association Mentor-Based Postdoctoral Fellowship Award #7-09-MN-32, all to Dr. Meigs, and NIDDK Research Career Award K23 DK65978, a Massachusetts General Hospital Physician Scientist Development Award and a Doris Duke Charitable Foundation Clinical Scientist Development Award to Dr. Florez; The FUSION study was supported by DK093757, DK072193, DK062370, and ZIA-HG000024. HAK has received funding from Academy of Finland (support for clinical research careers, grant no 258753); Support for GENOA was provided by the National Heart, Lung and Blood Institute (HL054464; HL054481; HL087660; HL119443; HL086694) of the National Institutes of Health; GIANT: Anne E Justice (AEJ) is funded under NIH 5K99HL130580-02; GLACIER: the current study was funded by Novo Nordisk, the Swedish Research Council, P\u00e5hlssons Foundation, the Swedish Heart Lung Foundation, and the Sk\u00e5ne Regional Health Authority (all to PWF); The Health, Aging, and Body Composition (HABC) Study is supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences; The HANDLS study was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (project # Z01-AG000513 and human subjects protocol number 09-AG-N248); HRS is supported by the National Institute on Aging (NIA U01AG009740).  The genotyping was funded separately by the National Institute on Aging (RC2 AG036495, RC4 AG039029); The Health2006 was financially supported by grants from the Velux Foundation; The Danish Medical Research Council, Danish Agency for Science, Technology and Innovation; The Aase and Ejner Danielsens Foundation; ALK-Abello A\/S, H\u00f8rsholm, Denmark, and Research Centre for Prevention and Health, the Capital Region of Denmark; The Health2008 was supported by the Timber Merchant Vilhelm Bang\u2019s Foundation, the Danish Heart Foundation (Grant number 07-10-R61-A1754-B838-22392F), and the Health Insurance Foundation (Helsefonden) (Grant number 2012B233); Heather M. Highland is supported by funding from NHLBI training grant T32 HL007055; Hidetoshi Kitajima was funded by Manpei Suzuki Diabetes Foundation Grant-in-Aid for the young scientists working abroad; Inter99: the study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation, and the Danish Diabetes Association; Funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197); Jennifer L. Asimit: Medical Research Council Methodology Research Fellowship (MR\/K021486\/1); The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung and Blood Institute and the National Institute on Minority Health and Health Disparities. ExomeChip genotyping was supported by the NHLBI of the National Institutes of Health under award number R01HL107816 to S. Kathiresan; Joel N. Hirschhorn: NIH R01DK075787; The KORA study was initiated and financed by the Helmholtz Zentrum M\u00fcnchen \u2013 German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was financed by a grant from the BMBF to the German Center for Diabetes Research (DZD) and a grant from the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (D\u00fcsseldorf, Germany). It was also supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universit\u00e4t, as part of LMUinnovativ; Leipzig Adults: this work was supported by grants from the German Research Council (SFB- 1052 \u201cObesity mechanisms\u201d; B01; B03), from the German Diabetes Association and from the DHFD (Diabetes Hilfs- und Forschungsfonds Deutschland). IFB AdiposityDiseases is supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501 (AD2-060E, AD2-06E99). This work was further supported by the Kompetenznetz Adipositas (Competence network for Obesity) funded by the Federal Ministry of Education and Research (German Obesity Biomaterial Bank; FKZ 01GI1128); Leipzig-Childhood-IFB: this work was supported by grants from Integrated Research and Treatment Centre (IFB) Adiposity Diseases, from the German Research Foundation for the Clinical Research Group \u201cAtherobesity\u201d KFO 152 (KO3512\/1 to AK), and by the European Commission (Beta-JUDO) and by EFRE (LIFE Child Obesity); Lothian Birth Cohort 1921 and Lothian Birth Cohort 1936: phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK\u2019s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project).  Genotyping was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, and the Royal Society of Edinburgh. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR\/K026992\/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged; MESA and the MESA SHARe projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420, UL1TR001881, DK063491, and R01HL105756.  Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278; The METSIM study was supported by the Academy of Finland (contract 124243), the Finnish Heart Foundation, the Finnish Diabetes Foundation, Tekes (contract 1510\/31\/06), and the Commission of the European Community (HEALTH-F2-2007 201681), and the US National Institutes of Health grants DK093757, DK072193, DK062370, and ZIA- HG000024; Natasha H J Ng (NHJN) is supported by the National Science Scholarship from the Agency for Science, Technology and Research (A*STAR) in Singapore; The genotyping in the NEO study was supported by the Centre National de G\u00e9notypage (Paris, France), headed by Jean-Francois Deleuze. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023); NFBC1966 and 1986 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NIHM (MH063706, Smalley and Jarvelin), Juselius Foundation,  NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH\/NIMH (5R01MH63706:02), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), ENGAGE project and grant agreement  HEALTH-F4-2007-201413, EU FP7 EurHEALTHAgeing -277849, the Medical Research Council, UK (G0500539, G0600705, G1002319,  PrevMetSyn\/SALVE) and the MRC, Centenary Early Career Award. The program is currently being funded by the H2020-633595 DynaHEALTH action and academy of Finland EGEA-project (285547). The DNA extractions, sample quality controls, biobank up-keeping and aliquotting was performed in the National Public Health Institute, Biomedicum Helsinki, Finland and supported financially by the Academy of Finland and Biocentrum Helsinki; The Botnia and The PPP-Botnia studies have been financially supported by grants from Folkhalsan Research Foundation, the Sigrid Juselius Foundation, The Academy of Finland and university of Helsinki (grants no. 263401, 267882, 312063, 312072 and 336826), the European Research Council under the European Union's Seventh Framework Programme (FP7\/2007-2013) \/ ERC grant agreement n\u00b0 269045, Nordic Center of Excellence in Disease Genetics, EU (EXGENESIS, MOSAIC FP7-600914), Ollqvist Foundation, Swedish Cultural Foundation in Finland, Finnish Diabetes Research Foundation, Foundation for Life and Health in Finland, Signe and Ane Gyllenberg Foundation, Finnish Medical Society, Paavo Nurmi Foundation, Helsinki University Central Hospital Research Foundation, Perkl\u00e9n Foundation, N\u00e4rpes Health Care Foundation and Ahokas Foundation. The study has also been supported by the Ministry of Education in Finland, Municipal Heath Care Center and Hospital in Jakobstad and Health Care Centers in Vasa, N\u00e4rpes and Korsholm; PROMIS: Dr. Saleheen has received grants from the National Heart, Lung and Blood Institute, Fogarty International, Pfizer, Regeneron, Eli Lilly, and Genentech; Robert Sladek is the recipient of a Chercheur Boursier award from the Fonds de la Recherche en Sant\u00e9 du Qu\u00e9bec and a New Investigator Award from the Canadian Institutes of Health Research and is supported by operating funds from the Canadian Institutes of Health Research; Rebecca Fine is supported by NHGRI F31 HG009850; The RISC study was supported by European Union grant QLG1-CT-2001-01252 and AstraZeneca. The initial genotyping of the RISC samples was funded by Merck & Co Inc.; Rona J Strawbridge is supported by a UKRI Innovation at HDR and University of Glasgow LKAS Fellowship; The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The Exome chip array data set was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)\/Netherlands Organisation for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), the Netherlands Organization for Scientific Research (NWO; project number 184021007) and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl (http:\/\/www.bbmri.nl)); SardiNIA: the study is supported by National Human Genome Research Institute grants HG005581, HG005552, HG006513, HG007022 and HG007089; by National Heart, Lung, and Blood Institute grant HL117626; by the Intramural Research Program of the US National Institutes of Health, National Institute on Aging, contracts N01-AG-1-2109 and HHSN271201100005C; by Sardinian Autonomous Region (L.R. 7\/2009) grant cRP3-154; The Singapore Chinese Eye Study was funded by the Agency for Science, Technology and Research - Biomedical Research Council (A*STAR BMRC) Grant, Singapore [08\/1\/35\/19\/550] and Singapore Ministry of Health\u2019s National Medical Research Council [NMRC\/CIRG\/1417\/2015]; Sorbs: this work was supported by grants from the German Research Council (DFG - SFB 1052 \u201cObesity mechanisms\u201d; A01, C01, B03 and SPP 1629 TO 718\/2-1), from the German Diabetes Association and from the DHFD (Diabetes Hilfs- und Forschungsfonds Deutschland); The UK Household Longitudinal Study is funded by the Economic and Social Research Council; The Vejle Diabetes Biobank was supported by The Danish Research Council for Independent Research; The WGHS is funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and National Cancer Institute (CA047988 and UM1CA182913). Funding for genotyping on the Exome Array was funded by Amgen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}