AMP T2D-GENES quantitative trait exome sequence analysis: European ancestry

Publications

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
Flannick J, et al.
Nature. 2019 May 22. doi: 10.1038/s41586-019-1231-2

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.
Flannick J, Fuchsberger C, Mahajan A, et al.
Sci Data. 2017 Dec 19;4:170179. doi: 10.1038/sdata.2017.179

The genetic architecture of type 2 diabetes.
Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ, et al.
Nature 2016 Aug 4;536(7614):41-7. doi: 10.1038/nature18642

Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.
SIGMA Type 2 Diabetes Consortium, et al.
JAMA. 2014 Jun 11;311(22):2305-14. doi: 10.1001/jama.2014.6511

Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes.
Lohmueller KE, et al.
Am J Hum Genet. 2013 Dec 5;93(6):1072-86. doi: 10.1016/j.ajhg.2013.11.005

Phenotypes

  • Adiponectin
  • BMI
  • Diastolic blood pressure
  • Fasting C-peptide
  • Fasting glucose
  • Fasting insulin
  • HbA1c
  • HDL cholesterol
  • Height
  • Hip circumference
  • HOMA-B
  • HOMA-IR
  • LDL cholesterol
  • Leptin 
  • Serum creatinine
  • Systolic blood pressure
  • Two-hour glucose
  • Two-hour insulin
  • Total cholesterol
  • Triglycerides
  • Triglyceride-to-HDL ratio
  • Waist circumference
  • Waist-hip ratio

Subjects

Project Cases Controls Cohort (Click to view selection criteria for cases and controls) Ancestry
ESP 389 2,842 Exome Sequencing Project (ESP) European
GoT2D 1,289 1,251 Multiple cohorts European
T2D-GENES 478 498 Metabolic Syndrome in Men Study (METSIM) European
T2D-GENES 506 360 Ashkenazi European
LuCAMP 992 985 Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care European
T2D-GENES 949 943 Genetics of Diabetes and Audit Research Tayside Study (GoDARTS) European
T2D-GENES 390 589 Framingham Heart Study (FHS) European

Projects

Exome Sequencing project (ESP) Learn more >

The Exome Sequencing Project (ESP) aims to discover novel genes and mechanisms contributing to heart, lung and blood disorders by pioneering the application of next-generation sequencing of the protein coding regions of the human genome across diverse, richly-phenotyped populations and to share these datasets and findings with the scientific community to extend and enrich the diagnosis, management and treatment of heart, lung and blood disorders.

Genetics of Type 2 Diabetes (GoT2D) Learn more >

The GoT2D consortium aims to understand the allelic architecture of type 2 diabetes through whole-genome sequencing, high-density SNP genotyping, and imputation. The reference panel based on this work is intended as a comprehensive inventory of low-frequency variants in Europeans, including SNPs, small insertions and deletions, and structural variants.

Lubeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp) Learn more >

The LuCamp research consortium aims to discover and characterize novel variation in the human genome conferring an increased risk of visceral obesity, type 2 diabetes and hypertension and eventually premature cardiovascular disorders and death; discover and characterize novel variation in the human gut microbiome influencing metabolic and cardiovascular health; investigate how the novel molecular signatures interact mutually and with other risk markers, particularly in health behavior, influencing the risk of developing widespread metabolic disorders; and investigate how these discoveries may help improve metabolic and cardiovascular health in the at-risk population.

Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Ethnic Samples (T2D-GENES) Learn more >

T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) is a large collaborative effort to find genetic variants that influence risk of type 2 diabetes. With funding from NIDDK, the group is pursuing three projects: (1) deep whole-exome sequencing in 10,000 people from five ethnicities (African-American, East Asian, South Asian, European, and Hispanic); (2) deep whole-genome sequencing of 600 individuals selected from extended Mexican American pedigrees; and (3) a trans-ethnic fine-mapping "mega-meta-analysis."

Overview of analysis and results

The T2D analysis reported in Flannick et al. 2019 was extended to 24 quantitative traits. Briefly, single-variant association analyses were conducted for each trait (n=24) at the sample sub-group level (n=25). We analyzed samples using the EMMAX test via the EPACTS software package. A genomic relationship matrix (GRM) was included to account for relatedness across samples. In all cases, multiallelic sites were categorized as a single "non-reference" allele.

For each of the 25 sub-studies × 24 traits (n=600) single-variant analyses, quantile-quantile (QQ)-plots of all and common (MAC>20) alleles were used to assess whether the regression models were well-calibrated (i.e., comparison of regression results to expected results under a null-model). Stringencies of the variant filters were increased based on digression from the null model. Variants were filtered based on sequencing quality or excessive heterozygosity. Covariates to adjust for subject ascertainment and/or differing sequencing technologies across sub-studies were added where appropriate. Phenotype-specific outliers were removed where appropriate. Following all sub-study level quality control, a 25-group fixed-effect inverse-variance weighted meta-analysis was then conducted using METAL.

contributing community
t2d
Dataset ID
ExSeq_52kQT_EU