Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the old order amish: Evidence for replication from diabetes-related quantitative traits and from independent populations

Evadnie Rampersaud, Coleen M. Damcott, Mao Fu, Haiqing Shen, Patrick McArdle, Xiaolian Shi, John Shelton, Jing Yin, Yen Pei C Chang, Sandra H. Ott, Li Zhang, Yiju Zhao, Braxton D. Mitchell, Jeffery O'Connell, Alan R. Shuldiner

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Abstract

OBJECTIVE - We sought to identify type 2 diabetes susceptibility genes through a genome-wide association scan (GWAS) in the Amish. RESEARCH DESIGN AND METHODS -DNA from 124 type 2 diabetic case subjects and 295 control subjects with normal glucose tolerance were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array. A total of 82,485 SNPs were tested for association with type 2 diabetes. Type 2 diabetes-associated SNPs were further prioritized by the following: 1) associations with 5 oral glucose tolerance test (OGTT) traits in 427 nondiabetic Amish subjects, and 2) in silico replication from three independent 100L SNP GWASs (Framingham Heart Study Caucasians, Pima Indians, and Mexican Americans) and a 500K GWAS in Scandinavians. RESULTS - The strongest association (P = 1.07 x 10-5) was for rs2237457, which is located in growth factor receptor-bound protein 10 (Grb10), an adaptor protein that regulate insulin receptor signaling. rs2237457 was also strongly associated with OGTT glucose area under the curve in nondiabetic subjects (P = 0.001). Of the 1,093 SNPs associated with type 2 diabetes at P < 0.01, 67 SNPs demonstrated associations with at least one OGTT trait in nondiabetic individuals; 80 SNPs were nominally associated with type 2 diabetes in one of the three independent 100K GWASs, 3 SNPs (rs2540317 in MFSD9, rs10515353 on chromosome 5, and rs2242400 in BCAT1 were associated with type 2 diabetes in more than one population), and 11 SNPs were nominally associated with type 2 diabetes in Scandinavians. One type 2 diabetes-associated SNP (rs3845971, located in FHIT) showed replication with OGTT traits and also in another population. CONCLUSIONS - Our GWAS of type 2 diabetes identified several gene variants associated with type 2 diabetes, some of which are worthy of further study.

Original languageEnglish
Pages (from-to)3053-3062
Number of pages10
JournalDiabetes
Volume56
Issue number12
DOIs
StatePublished - Dec 1 2007

Fingerprint

Amish
Genome-Wide Association Study
Genetic Association Studies
Type 2 Diabetes Mellitus
Single Nucleotide Polymorphism
Population
Glucose Tolerance Test
GRB10 Adaptor Protein
Potassium Iodide
Glucose
Chromosomes, Human, Pair 5
Insulin Receptor
Computer Simulation
Genes
Area Under Curve
Research Design

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the old order amish : Evidence for replication from diabetes-related quantitative traits and from independent populations. / Rampersaud, Evadnie; Damcott, Coleen M.; Fu, Mao; Shen, Haiqing; McArdle, Patrick; Shi, Xiaolian; Shelton, John; Yin, Jing; Chang, Yen Pei C; Ott, Sandra H.; Zhang, Li; Zhao, Yiju; Mitchell, Braxton D.; O'Connell, Jeffery; Shuldiner, Alan R.

In: Diabetes, Vol. 56, No. 12, 01.12.2007, p. 3053-3062.

Research output: Contribution to journalArticle

Rampersaud, E, Damcott, CM, Fu, M, Shen, H, McArdle, P, Shi, X, Shelton, J, Yin, J, Chang, YPC, Ott, SH, Zhang, L, Zhao, Y, Mitchell, BD, O'Connell, J & Shuldiner, AR 2007, 'Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the old order amish: Evidence for replication from diabetes-related quantitative traits and from independent populations', Diabetes, vol. 56, no. 12, pp. 3053-3062. https://doi.org/10.2337/db07-0457
Rampersaud, Evadnie ; Damcott, Coleen M. ; Fu, Mao ; Shen, Haiqing ; McArdle, Patrick ; Shi, Xiaolian ; Shelton, John ; Yin, Jing ; Chang, Yen Pei C ; Ott, Sandra H. ; Zhang, Li ; Zhao, Yiju ; Mitchell, Braxton D. ; O'Connell, Jeffery ; Shuldiner, Alan R. / Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the old order amish : Evidence for replication from diabetes-related quantitative traits and from independent populations. In: Diabetes. 2007 ; Vol. 56, No. 12. pp. 3053-3062.
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abstract = "OBJECTIVE - We sought to identify type 2 diabetes susceptibility genes through a genome-wide association scan (GWAS) in the Amish. RESEARCH DESIGN AND METHODS -DNA from 124 type 2 diabetic case subjects and 295 control subjects with normal glucose tolerance were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array. A total of 82,485 SNPs were tested for association with type 2 diabetes. Type 2 diabetes-associated SNPs were further prioritized by the following: 1) associations with 5 oral glucose tolerance test (OGTT) traits in 427 nondiabetic Amish subjects, and 2) in silico replication from three independent 100L SNP GWASs (Framingham Heart Study Caucasians, Pima Indians, and Mexican Americans) and a 500K GWAS in Scandinavians. RESULTS - The strongest association (P = 1.07 x 10-5) was for rs2237457, which is located in growth factor receptor-bound protein 10 (Grb10), an adaptor protein that regulate insulin receptor signaling. rs2237457 was also strongly associated with OGTT glucose area under the curve in nondiabetic subjects (P = 0.001). Of the 1,093 SNPs associated with type 2 diabetes at P < 0.01, 67 SNPs demonstrated associations with at least one OGTT trait in nondiabetic individuals; 80 SNPs were nominally associated with type 2 diabetes in one of the three independent 100K GWASs, 3 SNPs (rs2540317 in MFSD9, rs10515353 on chromosome 5, and rs2242400 in BCAT1 were associated with type 2 diabetes in more than one population), and 11 SNPs were nominally associated with type 2 diabetes in Scandinavians. One type 2 diabetes-associated SNP (rs3845971, located in FHIT) showed replication with OGTT traits and also in another population. CONCLUSIONS - Our GWAS of type 2 diabetes identified several gene variants associated with type 2 diabetes, some of which are worthy of further study.",
author = "Evadnie Rampersaud and Damcott, {Coleen M.} and Mao Fu and Haiqing Shen and Patrick McArdle and Xiaolian Shi and John Shelton and Jing Yin and Chang, {Yen Pei C} and Ott, {Sandra H.} and Li Zhang and Yiju Zhao and Mitchell, {Braxton D.} and Jeffery O'Connell and Shuldiner, {Alan R.}",
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T2 - Evidence for replication from diabetes-related quantitative traits and from independent populations

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AU - Damcott, Coleen M.

AU - Fu, Mao

AU - Shen, Haiqing

AU - McArdle, Patrick

AU - Shi, Xiaolian

AU - Shelton, John

AU - Yin, Jing

AU - Chang, Yen Pei C

AU - Ott, Sandra H.

AU - Zhang, Li

AU - Zhao, Yiju

AU - Mitchell, Braxton D.

AU - O'Connell, Jeffery

AU - Shuldiner, Alan R.

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N2 - OBJECTIVE - We sought to identify type 2 diabetes susceptibility genes through a genome-wide association scan (GWAS) in the Amish. RESEARCH DESIGN AND METHODS -DNA from 124 type 2 diabetic case subjects and 295 control subjects with normal glucose tolerance were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array. A total of 82,485 SNPs were tested for association with type 2 diabetes. Type 2 diabetes-associated SNPs were further prioritized by the following: 1) associations with 5 oral glucose tolerance test (OGTT) traits in 427 nondiabetic Amish subjects, and 2) in silico replication from three independent 100L SNP GWASs (Framingham Heart Study Caucasians, Pima Indians, and Mexican Americans) and a 500K GWAS in Scandinavians. RESULTS - The strongest association (P = 1.07 x 10-5) was for rs2237457, which is located in growth factor receptor-bound protein 10 (Grb10), an adaptor protein that regulate insulin receptor signaling. rs2237457 was also strongly associated with OGTT glucose area under the curve in nondiabetic subjects (P = 0.001). Of the 1,093 SNPs associated with type 2 diabetes at P < 0.01, 67 SNPs demonstrated associations with at least one OGTT trait in nondiabetic individuals; 80 SNPs were nominally associated with type 2 diabetes in one of the three independent 100K GWASs, 3 SNPs (rs2540317 in MFSD9, rs10515353 on chromosome 5, and rs2242400 in BCAT1 were associated with type 2 diabetes in more than one population), and 11 SNPs were nominally associated with type 2 diabetes in Scandinavians. One type 2 diabetes-associated SNP (rs3845971, located in FHIT) showed replication with OGTT traits and also in another population. CONCLUSIONS - Our GWAS of type 2 diabetes identified several gene variants associated with type 2 diabetes, some of which are worthy of further study.

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