title: Joint effects of known type 2 diabetes susceptibility loci in genome-wide association study of Singapore Chinese: the Singapore Chinese health study.
abstract: BACKGROUND
  Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study.
  
  
  METHODS
  2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r(2)>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ± 100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis.
  
  
  RESULTS
  Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69-2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72 × 10(-14)). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs.
  
  
  CONCLUSIONS
  While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment interactions complicate the genetic architecture of this disease.
authors: Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Zhanghua
authors: Z
authors: Chen
authors: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Mark A
authors: MA
authors: Pereira
authors: Department of Laboratory Medicine, Department of Epidemiology and Biostatistics, and California Institute for Quantitative Biosciences (QB3), University of California San Francisco, San Francisco, California, United States of America.
authors: Mark
authors: M
authors: Seielstad
authors: Duke-National University of Singapore Graduate Medical School, Singapore ; Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
authors: Woon-Puay
authors: WP
authors: Koh
authors: Duke-National University of Singapore Graduate Medical School, Singapore ; Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
authors: E Shyong
authors: ES
authors: Tai
authors: Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
authors: Yik-Ying
authors: YY
authors: Teo
authors: Saw Swee Hock School of Public Health, National University of Singapore, Singapore ; Human Genetics, Genome Institute of Singapore, ASTAR, Singapore.
authors: Jianjun
authors: J
authors: Liu
authors: Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Chris
authors: C
authors: Hsu
authors: Department of Epidemiology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors: Renwei
authors: R
authors: Wang
authors: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Andrew O
authors: AO
authors: Odegaard
authors: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Bharat
authors: B
authors: Thyagarajan
authors: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Revati
authors: R
authors: Koratkar
authors: Department of Epidemiology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors: Jian-Min
authors: JM
authors: Yuan
authors: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Myron D
authors: MD
authors: Gross
authors: Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Daniel O
authors: DO
authors: Stram
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006262:Health; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012846:Singapore