A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants

Scott, Laura J.; Mohlke, Karen L.; Bonnycastle, Lori L.; Willer, Cristen J.; Li, Yun; Duren, William L.; Erdos, Michael R.; Stringham, Heather M.; Chines, Peter S.; Jackson, Anne; Prokunina‐Olsson, Ludmila; Ding, Chia-Jen; Swift, Amy J.; Narisu, Narisu; Hu, Tianle; Pruim, Randall; Xiao, Rui; Li, Xiaoyi; Conneely, Karen N.; Riebow, Nancy L.; Sprau, Andrew G.; Tong, Maurine; White, Peggy P.; Hetrick, Kurt N.; Barnhart, Michael W.; Bark, Craig W.; Goldstein, Janet L.; Watkins, Lee; Fang, Xiang; Saramies, Jouko; Buchanan, Thomas A.; Watanabe, Richard M.; Valle, Timo T.; Kinnunen, Leena; Abecasis, Gonçalo R.; Pugh, Elizabeth; Doheny, Kimberly F.; Bergman, Richard N.; Tuomilehto, Jaakko; Collins, Francis S.; Boehnke, Michael

doi:10.1126/science.1142382

Cited by 2,506 publications

(2,006 citation statements)

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“…Nevertheless, its potential function of regulating the HHEX gene was suspected from previous genome-wide association studies in which several variants including the rs5015480 in and around the gene have been associated with T2DM of Europeans. 2,3,5 The associations were replicated also in the Japanese 17 and the Chinese 12 populations. Furthermore, other variants of the gene were associated with impaired pancreatic b-cell function and thus with decreased insulin secretion.…”

Section: Discussionmentioning

confidence: 65%

“…Especially, several genome-wide association studies were recently conducted. [1][2][3][4][5] Nevertheless, their results revealed inconsistencies in associations of many nucleotide sequence variants. 6 A serious publication bias was suspected because a fewer publications with negative results were likely to be reported from candidate gene association analyses.…”

Section: Introductionmentioning

confidence: 99%

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Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

et al. 2011

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We examined the genetic associations of previously identified sequence variants with type 2 diabetes mellitus (T2DM) and its potentially genetic heterogeneity by gender in a large-scale cohort. A total of 613 T2DM patients and 8221 control subjects from the Korea Association REsource (KARE) cohort were included in the analysis of genetic association of T2DM with 33 nucleotide polymorphic markers identified by previous studies. The association analysis was further conducted with data partitioned by gender. The association analysis resulted in five nucleotide sequence variants associated with the susceptibility of T2DM after Bonferonni correction (Po0.0015). One was located near the gene of hematopoietically expressed homeobox (HHEX), and the others were all in the gene of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1). Further analysis revealed that the sequence variant (rs5015480) near HHEX and two SNPs (rs7756992 and rs9465871) in CDKAL1 were associated with the susceptibility of T2DM in females (Po0.005), but not in males (P40.005). We suggested heterogeneous genetic associations of the T2DM susceptibility with the CDKAL1 and HHEX genes by gender.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

et al. 2011

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“…within or close to FTO, CDKN2A/B, IGF2BP2, SLC30A8, CDKAL1 and HHEX/IDE, along with confirming the involvement of TCF7L2, PPARG and KCNJ11 [1][2][3][4][5][6]. Many of the confirmed type 2 diabetes variants have since been shown in population cohorts to alter beta cell function [7][8][9][10][11][12][13].…”

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confidence: 73%

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

et al. 2008

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Aims/hypothesis Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. Methods A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. Results The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min −1 m −2 (mmol/l) −1 , p=1.51×10 −6 ). The same was seen for the 30 min insulin response (p=4.17×10 −7 ). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p<0.001 and p=0.003, respectively).Conclusions/interpretation This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in nondiabetic individuals.

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“…These newly identified loci were not previously suspected for T2D. [49][50][51][52][53] Four smaller GWAS of T2D were also published in that year, but did not produce any significant findings. Before the GWAS era, only two genes (PPAGg and KCNJ11) have been consistently associated with this metabolic disorder, one of which, the TCF7L2 gene, was identified through linkage analysis and fine mapping.…”

Section: The Year Of Gwas: 2007mentioning

confidence: 99%

The pursuit of genome-wide association studies: where are we now?

et al. 2010

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It is now 5 years since the first genome-wide association studies (GWAS), published in 2005, identified a common risk allele with large effect size for age-related macular degeneration in a small sample set. Following this exciting finding, researchers have become optimistic about the prospect of the genome-wide association approach. However, most of the risk alleles identified in the subsequent GWAS for various complex diseases are common with small effect sizes (odds ratio o1.5). So far, more than 450 GWAS have been published and the associations of greater than 2000 single nucleotide polymorphisms (SNPs) or genetic loci were reported. The aim of this review paper is to give an overview of the evolving field of GWAS, discuss the progress that has been made by GWAS and some of the interesting findings, and summarize what we have learned over the past 5 years about the genetic basis of human complex diseases. This review will focus on GWAS of SNPs association for complex diseases but not studies of copy number variations.

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A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants

Cited by 2,506 publications

References 31 publications

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

The pursuit of genome-wide association studies: where are we now?

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