T2D-GENES Multi-Ethnic Exome Sequencing Study: UK South Asian

T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The London Life Sciences Population Study (LOLIPOP) contributed 530 cases and 538 controls to T2D-GENES Project 1. ]]>
Cases were ascertained according to the following criteria: Samples were chosen from a population-based cohort study. Indian Asians living in West London, UK, with all 4 grandparents born on the Indian subcontinent. Prevalent T2D defined as previous physician diagnosis of diabetes on treatment, with onset of diabetes after the age of 18 years and without insulin use in the first year after diagnosis; or fasting plasma glucose >/=7.0 mmol/L. Controls were determined according to the following criteria: No previous history of diabetes. No anti-diabetic medication. Fasting plasma glucose <6.0 mmol/L. Samples with age of onset <18 excluded.]]>
T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. The organizations involved in the NIDDK U01 include: Broad Institute, University of Michigan, University of Oxford, NIDDK/NIH, University of Chicago, Texas Biomedical Research Institute, Massachusetts General Hospital, University of Texas Health Science Center, University of North Carolina, Blood Systems Research Institute, and University of Mississippi Medical Center. The T2D-GENES collaboration effort consists of 3 projects: Project 1 seeks to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. Project 2 is focused on the role of rare and private variants on T2D risk, and is based on deep whole genome sequencing of ~600 members of 20 Mexican American pedigrees. Pedigree members are extensively phenotyped and have been genotyped with Illumina GWAS chips. Project 3 seeks to determine whether multiethnic GWAS meta-analysis might assist in fine-mapping T2D association signals by strengthening evidence for T2D association and narrowing the association interval. Project 3 has focused initially on analysis of five T2D loci chosen as likely candidates for success of this approach. This submission reflects the activities that occurred in T2D-GENES Project 1. Each of the studies involved in T2D-GENES Project1 are part of larger cohorts. While each participating cohort has specific cohort information and history, that information is not summarized here as we have specifically selected these samples for type 2 diabetes research as part of the T2D-GENES study. For more information on these studies, please see table 2. Table 2. Studies contributing samples to T2D-GENES Project 1 Study Name PI(s) Study URL (if available) Jackson Heart Study Candidate Gene Association Resource Jim Wilson http://www.jacksonheartstudy.org Wake Forest Study Donald Bowden Korea Association Research Project (KARE) and Korean National Institute of Health (KNIH) Jong-Young Lee and Yoon Shin Cho Singapore Diabetes Cohort Study and Singapore Prospective Study Program Daniel Ng Peng Keat and Tai E. Shyong http://www.nus-cme.org.sg/about.html Longevity Genes in Founder Populations (Ashkenazi) Nir Barzilai, Gil Atzmon http://www.einstein.yu.edu/centers/aging/longevity-genes-project/ ]]>

T2D-GENES（多族群样本下一代测序2型糖尿病基因探索研究，Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples）是由美国国家糖尿病、消化与肾脏疾病研究所（National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK）资助的国际研究联盟，旨在通过多族群测序研究识别2型糖尿病（Type 2 Diabetes, T2D）的遗传变异。

T2D-GENES项目1为一项多族群测序研究，旨在评估低频变异是否参与2型糖尿病患病风险，并解析不同祖先人群中2型糖尿病风险变异分布的异同。研究对象来自表1所列的14个队列。本次研究采用的策略为对12940名个体开展深度外显子测序，其中6504名2型糖尿病患者与6436名健康对照，样本被划分为5个祖先族群：欧洲人、东亚人、南亚人、美国西班牙裔及非裔美国人。测序工作由博德研究所（Broad Institute）在Illumina HiSeq测序平台上使用安捷伦v2捕获试剂完成。

请注意，尽管本研究在出版物及下文汇总了全部样本列表，但奥格斯堡地区合作健康研究（Kooperative Gesundheitsforschung in der Region Augsburg, KORA）未设置子研究，因其未获得存入基因型与表型数据库（dbGAP）的知情同意。

表1. T2D-GENES全外显子测序研究
祖先分组 研究名称 起源国家 病例数 对照数
非裔美国人 杰克逊心脏研究 美国 502 527
非裔美国人 维克森林医学院研究 美国 518 532
东亚人 韩国关联研究项目 韩国 526 561
东亚人 新加坡糖尿病队列研究与新加坡前瞻性研究计划 新加坡（华裔） 486 592
欧洲人 德系阿什肯纳兹人群研究 美国、以色列 506 352
欧洲人 男性代谢综合征研究（METSIM） 芬兰 484 498
欧洲人 芬兰-美国非胰岛素依赖型糖尿病遗传学研究（FUSION） 芬兰 472 476
欧洲人 奥格斯堡地区合作健康研究（KORA） 德国 97 90
欧洲人 英国2型糖尿病遗传学联盟（UKT2D） 英国 322 320
欧洲人 马尔默-博特尼亚研究 芬兰、瑞典 478 443
西班牙裔 圣安东尼奥家庭心脏研究、圣安东尼奥家庭糖尿病/胆囊研究、退伍军人事务部遗传流行病学研究及肾病与糖尿病研究家族组成部分 美国 272 219
西班牙裔 德克萨斯州斯塔尔县研究 美国 749 704
南亚人 伦敦生命科学人群研究（LOLIPOP） 英国（印度裔亚洲人） 530 538
南亚人 新加坡印度裔眼部研究 新加坡（印度裔亚洲人） 563 585

伦敦生命科学人群研究（LOLIPOP）为T2D-GENES项目1提供了530例病例与538名对照。

病例与对照的入组标准如下：
### 病例入组标准
样本取自基于人群的队列研究。研究对象为居住于英国西伦敦的印度裔亚洲人，其4名祖父母均出生于印度次大陆。2型糖尿病患病定义为：经医师确诊的既往糖尿病且需药物治疗，糖尿病发病年龄≥18岁且确诊后1年内未使用胰岛素；或空腹血浆葡萄糖≥7.0 mmol/L。

### 对照入组标准
无糖尿病既往史，未使用抗糖尿病药物，空腹血浆葡萄糖<6.0 mmol/L。发病年龄<18岁的样本予以排除。

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T2D-GENES（多族群样本下一代测序2型糖尿病基因探索研究）是由NIDDK资助的国际研究联盟，旨在通过多族群测序研究识别2型糖尿病的遗传变异。参与NIDDK U01项目的机构包括：博德研究所、密歇根大学、牛津大学、美国国家糖尿病、消化与肾脏疾病研究所/美国国立卫生研究院（NIDDK/NIH）、芝加哥大学、德克萨斯生物医学研究所、麻省总医院、德克萨斯大学健康科学中心、北卡罗来纳大学、血液系统研究所以及密西西比大学医学中心。

T2D-GENES合作项目包含3个子项目：
1. 项目1：旨在评估低频变异是否参与2型糖尿病患病风险，并解析不同祖先人群中2型糖尿病风险变异分布的异同。
2. 项目2：聚焦罕见变异与私有变异对2型糖尿病患病风险的作用，基于对20个墨西哥裔美国家系的约600名成员开展深度全基因组测序。家系成员均接受了全面的表型分型，并使用Illumina全基因组关联研究（GWAS）芯片进行基因分型。
3. 项目3：旨在探究多族群全基因组关联研究元分析是否可通过强化2型糖尿病关联证据、缩小关联区间来辅助精细定位2型糖尿病关联信号。项目3最初优先分析了5个被认为适合该研究方法的2型糖尿病易感位点。

本次提交内容反映了T2D-GENES项目1的相关研究活动。参与T2D-GENES项目1的各项研究均隶属于更大的队列。尽管每个参与队列均有其专属的队列信息与研究背景，但由于本研究为T2D-GENES研究中的2型糖尿病专门筛选了样本，因此此处未汇总相关信息。如需了解这些研究的更多详情，请参阅表2。

表2. 为T2D-GENES项目1提供样本的研究
研究名称 主要研究者（PI） 研究网址（如有）
杰克逊心脏研究（候选基因关联资源） Jim Wilson http://www.jacksonheartstudy.org
维克森林研究 Donald Bowden 无
韩国关联研究项目（KARE）与韩国国立卫生研究院（KNIH） Jong-Young Lee与Yoon Shin Cho 无
新加坡糖尿病队列研究与新加坡前瞻性研究计划 Daniel Ng Peng Keat与Tai E. Shyong http://www.nus-cme.org.sg/about.html
创始人群长寿基因研究（德系阿什肯纳兹人群） Nir Barzilai、Gil Atzmon http://www.einstein.yu.edu/centers/aging/longevity-genes-project/