A genome–wide search for human non–insulin–dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2

Hanis, Craig L.; Boerwinkle, Eric; Chakraborty, Ranajit; Ellsworth, Darrell L.; Concannon, Patrick; Stirling, Brigid; Morrison, V. Anne; Wapelhorst, Beth; Spielman, Richard S.; Gogolin-Ewens, K J; Shephard, James; Williams, Sloan R.; Risch, Neil; Hinds, David A.; Iwasaki, Naoko; Ogata, Makiko; Omori, Yasue; Petzold, C; Rietzsch, Hannes; Schröder, H.-E.; Schulze, Jan; Cox, Nancy J.; Menzel, Stephan; Boriraj, V. Vicky; Chen, X.; Lim, Lauren; Lindner, Tom H.; Mereu, Laurie; Wang, Y. Q.; Xiang, Kun–san; Yamagata, Kazuya; Yang, Yan; Bell, Graeme I.

doi:10.1038/ng0696-161

Cited by 546 publications

(319 citation statements)

References 32 publications

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“…In the first successful genome-wide scan of a complex disease like type 2 diabetes Graeme Bell and co-workers reported in 1996 significant linkage of T2D in Mexican American sib pairs to a locus on chromosome 2q37, which is called NIDDM1 (15). A re-examination of the data suggested an interaction with another locus on chromosome 15 (16).…”

Section: Calpain 10 and Type 2 Diabetesmentioning

confidence: 99%

Genetic dissection of type 2 diabetes

Ridderstråle¹,

Groop²

2009

Molecular and Cellular Endocrinology

122

114

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Compared to the successful probing of genetic causes of monogenic disorders, dissecting the genetics of complex polygenic diseases has until recently been a fairly slow and cumbersome process. With the introduction of whole genome wide association studies (WGAS) the situation dramatically changed in 2007. The results from several recent WGAS on type 2 diabetes (T2D) and obesity have identified at least eighteen genes consistently associated with T2D. Many of the genes implicate pancreatic beta-cell function in the pathogenesis of T2D whereas only one clearly associate with insulin resistance. The identified genes most likely merely represent the tip of the iceberg in the explanation behind T2D. Refined tools will have to provide a more complete picture of the genetic complexity of T2D over the next few years. In addition to common variants increasing susceptibility for the disease, rare variants with stronger effects, copy number variations, and epigenetic effects like DNA methylation and histone acetylation will become important. Nevertheless, today we are able for the first time to anticipate that the genetics of a complex disease like T2D really can be dissected. Key wordsgenetics, complex disease, monogenic, polygenic, linkage study, genome wide scan, association study, single nucleotide polymorphism, epigenetic, type 2 diabetes, obesity. Evidence that type 2 diabetes is inheritedThere is ample evidence that T2D has a strong genetic component. The concordance of T2D in monozygotic twins is approximately 70% compared with 20-30% in dizygotic twins (1,2). Given the age-dependent penetrance of the disease, it is clear that the longer the follow-up, the higher the concordance rate (2). T2D clusters in families. The life-time risk of developing the disease is about 40% in offspring of one parent with T2D (3), greater if the mother is affected (4), the risk approaching 70% if both parents have diabetes. Translated into a s-value, the recurrence risk for a sibling of an affected person divided by the risk for the general population, this means that a first-degree relative of a patient with type 2 diabetes has a 3-fold increased risk of developing the disease (5). Large ethnic differences in the prevalence of T2D have also been ascribed to a genetic component (6,7). The change in the environment towards a more affluent Western life style plays a key role in the epidemic increase in the prevalence of T2Dworldwide. This change has occurred during the last 50 years. Clearly, our genes have not changed during this period but this does not exclude an important role for genes in the rapid increase in T2D, since genes or gene variants explain how we respond to the environment. Page 4 of 25A c c e p t e d M a n u s c r i p t 4 Thrifty genotypes or phenotypes?A plausible explanation for the interaction between genes and environment comes from the thrifty gene hypothesis. Neel (8) proposed that individuals living in an environment with unstable food supply (as for hunters and nomads) would maximize their probabilit...

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Section: Calpain 10 and Type 2 Diabetesmentioning

confidence: 99%

Genetic dissection of type 2 diabetes

Ridderstråle¹,

Groop²

2009

Molecular and Cellular Endocrinology

122

114

View full text Add to dashboard Cite

show abstract

“…Common variants in the CAPN10 gene are associated with transcript levels in skeletal muscle and adipose tissue [48]. Studies on MexicanAmerican affected sibpairs indicated the susceptibility locus for NIDDM was chromosome 2q37 and the locus was designated as NIDDM1 [49]. NIDDM1 locus was known to interact with a locus on chromosome 15q21 contributing to NIDDM in Mexican-Americans [50].…”

Section: Calpains and Niddmmentioning

confidence: 99%

The calpain system and diabetes

et al. 2014

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“…In this study, we selected a target region on chromosome 3p24.3-22.1 that corresponds to 20.4 Mb based on replicated linkage for type 2 diabetes or its related traits [6,[12][13][14][15][16]. We adopted a two-step association test using 1,762 Japanese subjects to reduce the time and cost of genotyping.…”

Section: Discussionmentioning

confidence: 99%

“…This was followed by SNPs-based fine-scale linkage disequilibrium (LD) and association mapping in the candidate region, supported by replicated linkage signals in Japanese and other multiple populations. In a number of candidate regions [5][6][7][8][9][10][11] for type 2 diabetes and its related traits, we selected the overlapping region on chromosome 3p24.3-22.1. This region showed nominal significance in linkage (maximum logarithm of the odds [lod] score=1.58) for type 2 diabetes in a Japanese population [12].…”

Section: Introductionmentioning

confidence: 99%

“…This region showed nominal significance in linkage (maximum logarithm of the odds [lod] score=1.58) for type 2 diabetes in a Japanese population [12]. In Japanese people, it was reported to substantially overlap with that in Mexican Americans [6,13] and with that reported in the American Diabetes Association's Genetics of NIDDM study in Mexican Americans [14]. These results in Mexican Americans were replicated in Pima Indians [15] and Finnish families [16] (Electronic supplementary material [ESM] Table 1).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population

et al. 2007

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Aims/hypothesis In order to identify type 2 diabetes disease susceptibility gene(s) in a Japanese population, we applied a region-wide case-control association test to the 20.4 Mb region between D3S1293 and D3S2319 on chromosome 3p24.3-22.1, supported by linkage to type 2 diabetes and its related traits in Japanese and multiple populations. Materials and methods We performed a two-stage association test using 1,762 Japanese persons with 485 gene-centric, evenly spaced, common single nucleotide polymorphism (SNP) markers with minor allele frequency >0.1. For mouse studies, total RNA was extracted from various organs of BKS.Cg-+Lepr db /+Lepr db and control mice, and from MIN6, NIH3T3 and C2C12 cell lines. Results We detected a landmark SNP375 (A/G) (rs2051211, p=0.000046, odds ratio=1.33, 95% CI 1.16-1.53) in intron 5 of the endonuclease G-like 1 (ENDOGL1) gene. Systematic dense SNPs approach identified a susceptibility linkage disequilibrium (LD) block of 116.5 kb by |D′|, an LD units map and a critical region of 2.1 kb by r 2 in ENDOGL1. A haplotype-based association test showed that an at-risk haplotype is associated with disease status (p= 0.00001). The expression of ENDOGL1 was rather ubiquitous with relatively abundant expression in the brain and Diabetologia

show abstract

A genome–wide search for human non–insulin–dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2

Cited by 546 publications

References 32 publications

Genetic dissection of type 2 diabetes

Genetic dissection of type 2 diabetes

The calpain system and diabetes

Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population

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