Potential etiologic and functional implications of genome-wide association loci for human diseases and traits

Hindorff, Lucia A.; Sethupathy, Praveen; Junkins, Heather; Ramos, Erin M.; Mehta, Jayashri P.; Collins, Francis S.; Manolio, Teri A.

doi:10.1073/pnas.0903103106

Cited by 3,748 publications

(3,580 citation statements)

References 19 publications

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“…Advances in genotyping technologies have facilitated genome-wide association studies and have contributed to the identification of thousands of SNPs associated with disease 1 . However, most of the associated SNPs explain a modest proportion of heritability for most common diseases, 2 and they do not provide variants directly applicable for diagnosis, prevention and treatment.…”

Section: Introductionmentioning

confidence: 99%

Fine-scale human genetic structure in Western France

Karakachoff¹,

Duforet-Frebourg²,

Simonet³

et al. 2014

Eur J Hum Genet

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The difficulties arising from association analysis with rare variants underline the importance of suitable reference population cohorts, which integrate detailed spatial information. We analyzed a sample of 1684 individuals from Western France, who were genotyped at genome-wide level, from two cohorts D.E.S.I.R and CavsGen. We found that fine-scale population structure occurs at the scale of Western France, with distinct admixture proportions for individuals originating from the Brittany Region and the Vendé e Department. Genetic differentiation increases with distance at a high rate in these two parts of Northwestern France and linkage disequilibrium is higher in Brittany suggesting a lower effective population size. When looking for genomic regions informative about Breton origin, we found two prominent associated regions that include the lactase region and the HLA complex. For both the lactase and the HLA regions, there is a low differentiation between Bretons and Irish, and this is also found at the genome-wide level. At a more refined scale, and within the Pays de la Loire Region, we also found evidence of fine-scale population structure, although principal component analysis showed that individuals from different departments cannot be confidently discriminated. Because of the evidence for fine-scale genetic structure in Western France, we anticipate that rare and geographically localized variants will be identified in future full-sequence analyses.

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Section: Introductionmentioning

confidence: 99%

Fine-scale human genetic structure in Western France

Karakachoff¹,

Duforet-Frebourg²,

Simonet³

et al. 2014

Eur J Hum Genet

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“…All the published GWAS have been cataloged in the National Human Genome Research Institute 'A Catalog of Published Genome-Wide Association Studies' (http://www.genome.gov/gwa studies/) and this resource includes only those studies that attempted to genotype at least 100 000 SNPs in the initial stage. 3 As a result, the AMD study by Klein et al 1 was recorded as the first entry in the catalog and was generally being recognized as the first GWAS.…”

Section: Gwas Before Hapmapmentioning

confidence: 99%

“…Instead, most of the disease-associated risk alleles conferred small effect sizes (OR o1.5). 2,3 The finding of not many large effect size variants is expected, as the purifying selection pressure will remove them from the populations or keep their population frequencies low. However, GWAS is not a powerful approach for studying rare or uncommon SNPs (regardless of their effect sizes), because they are poorly represented in the commercial whole genome genotyping arrays.…”

Section: Introductionmentioning

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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“…11 GWAS and meta-analysis of GWAS have also identified metabolic syndrome trait-associated genetic variations, including obesity, type 2 diabetes, dyslipidemia and hypertension. 12 We have previously reported that among the single-nucleotide polymorphisms (SNPs) susceptible to obesity, [13][14][15] rs7498665 in the SH2B adaptor protein 1 (SH2B1) gene was associated with VFA, 16 and that among hypertension-susceptible SNPs, 17,18 rs1004467 in the cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1) gene and rs11191548 in the 5¢-nucleotidase, cytosolic II (NT5C2) gene were significantly associated with both reduced VFA and SFA in women, indicating a genetic background to central obesity. 19 Visceral fat obesity is also a risk factor for the development of type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Association between type 2 diabetes genetic susceptibility loci and visceral and subcutaneous fat area as determined by computed tomography

Hotta

Kitamoto

et al. 2012

J Hum Genet

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Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P¼0.00088 and P¼0.0010, respectively) and SFA (P¼0.00013 and P¼0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power.

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Potential etiologic and functional implications of genome-wide association loci for human diseases and traits

Abstract: catalog ͉ evolution ͉ GWAS ͉ polymorphism ͉ disorders

Cited by 3,748 publications

References 19 publications

Fine-scale human genetic structure in Western France

Fine-scale human genetic structure in Western France

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

Association between type 2 diabetes genetic susceptibility loci and visceral and subcutaneous fat area as determined by computed tomography

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