| 1. |
- Campbell, C D, et al.
(författare)
-
Demonstrating stratification in a European American population
- 2005
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 37:8, s. 868-872
-
Tidskriftsartikel (refereegranskat)abstract
- Population stratification occurs in case-control association studies when allele frequencies differ between cases and controls because of ancestry. Stratification may lead to false positive associations, although this issue remains controversial(1-4). Empirical studies have found little evidence of stratification in European-derived populations, but potentially significant levels of stratification could not be ruled out(5-7). We studied a European American panel discordant for height, a heritable trait that varies widely across Europe(8). Genotyping 178 SNPs and applying standard analytical methods(6,9-11) yielded no evidence of stratification. But a SNP in the gene LCT that varies widely in frequency across Europe(12) was strongly associated with height (P < 10(-6)). This apparent association was largely or completely due to stratification; rematching individuals on the basis of European ancestry greatly reduced the apparent association, and no association was observed in Polish or Scandinavian individuals. The failure of standard methods to detect this stratification indicates that new methods may be required.
|
|
| 2. |
- Florez, J. C., et al.
(författare)
-
Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes
- 2007
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:6, s. 1209-1217
-
Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal. Subjects and methods We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects. Results In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p=0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p=0.059). The combined OR was 1.20 (p=0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits. Conclusion/interpretation Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
|
|
| 3. |
- Florez, J C, et al.
(författare)
-
Association testing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people
- 2005
-
Ingår i: Diabetes. - 1939-327X. ; 54:6, s. 1884-1891
-
Tidskriftsartikel (refereegranskat)abstract
- Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, inactivates the insulin signal transduction cascade by dephosphorylating phosphotyrosine residues in insulin signaling molecules. Due to its chromosomal location under a chromosome 20 linkage peak and the metabolic effects of its absence in knockout mice, it is a candidate gene for type 2 diabetes. Recent studies have associated common sequence variants in PTPN1 with type 2 diabetes and diabetes-related phenotypes. We sought to replicate the association of common single nucleotide polymorphisms (SNPs) and haplotypes in PTPN1 with type 2 diabetes, fasting plasma glucose, and insulin sensitivity in a large collection of subjects. We assessed linkage disequilibrium, selected tag SNPs, and typed these markers in 3,347 cases of type 2 diabetes and 3,347 control subjects as well as 1,189 siblings discordant for type 2 diabetes. Despite power estimated at > 95% to replicate the previously reported associations, no statistically significant evidence of association was observed between PTPN1 SNPs or common haplotypes with type 2 diabetes or with diabetic phenotypes.
|
|
| 4. |
- Purcell, Shaun M., et al.
(författare)
-
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
- 2009
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 460:7256, s. 748-752
-
Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
|
|
| 5. |
- Saxena, R, et al.
(författare)
-
Comprehensive association testing of common mitochondrial DNA variation in metabolic disease
- 2006
-
Ingår i: American Journal of Human Genetics. - 0002-9297. ; 79:1, s. 54-61
-
Tidskriftsartikel (refereegranskat)abstract
- Many lines of evidence implicate mitochondria in phenotypic variation: ( a) rare mutations in mitochondrial proteins cause metabolic, neurological, and muscular disorders; ( b) alterations in oxidative phosphorylation are characteristic of type 2 diabetes, Parkinson disease, Huntington disease, and other diseases; and ( c) common missense variants in the mitochondrial genome ( mtDNA) have been implicated as having been subject to natural selection for adaptation to cold climates and contributing to "energy deficiency" diseases today. To test the hypothesis that common mtDNA variation influences human physiology and disease, we identified all 144 variants with frequency > 1% in Europeans from > 900 publicly available European mtDNA sequences and selected 64 tagging single-nucleotide polymorphisms that efficiently capture all common variation ( except the hypervariable D-loop). Next, we evaluated the complete set of common mtDNA variants for association with type 2 diabetes in a sample of 3,304 diabetics and 3,304 matched nondiabetic individuals. Association of mtDNA variants with other metabolic traits ( body mass index, measures of insulin secretion and action, blood pressure, and cholesterol) was also tested in subsets of this sample. We did not find a significant association of common mtDNA variants with these metabolic phenotypes. Moreover, we failed to identify any physiological effect of alleles that were previously proposed to have been adaptive for energy metabolism in human evolution. More generally, this comprehensive association-testing framework can readily be applied to other diseases for which mitochondrial dysfunction has been implicated.
|
|
| 6. |
- Saxena, Richa, et al.
(författare)
-
Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
- 2007
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
-
Tidskriftsartikel (refereegranskat)abstract
- New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
|
|
| 7. |
- Winckler, W, et al.
(författare)
-
Association of common variation in the HNF1 alpha gene region with risk of type 2 diabetes
- 2005
-
Ingår i: Diabetes. - 1939-327X. ; 54:8, s. 2336-2342
-
Tidskriftsartikel (refereegranskat)abstract
- It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1 alpha, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1a with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1 alpha, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in > 4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from the coding region and 5' of the gene demonstrated nominal association with type 2 diabetes, with the most significant marker (rs1920792) having an odds ratio of 1.17 and a P value of 0.002. We then genotyped three SNPs with the strongest evidence for association to type 2 diabetes (rs1920792, I27L, and A98V) in an additional 4,400 type 2 diabetic and control subjects from North America and Poland and compared our results with those of the original sample and of Weedon et al. None of the results were consistently observed across all samples, with the possible exception of a modest association of the rare (3-5%) A98V variant. These results indicate that common variants in HNF1 alpha either play no role in type 2 diabetes, a very small role, or a role that cannot be consistently observed without consideration of as yet unmeasured genetic or environmental modifiers.
|
|
| 8. |
- Winckler, W, et al.
(författare)
-
Association testing of variants in the hepatocyte nuclear factor 4 alpha gene with risk of type 2 diabetes in 7,883 people
- 2005
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 54:3, s. 886-892
-
Tidskriftsartikel (refereegranskat)abstract
- Two recent publications reported association of common polymorphisms in the P2 promoter of hepatocyte nuclear factor 4alpha (HNF4alpha) (the MODY1 gene) with risk for type 2 diabetes. We attempted to reproduce this putative association by genotyping 11 single nucleotide polymorphism (SNPs) spanning the HNF4a coding region and the P2 promoter in >3,400 patients and control subjects from Sweden, Finland, and Canada. One SNP that was consistently associated in the two previous reports (rs1884613, in the P2 promoter region) also trended in the same direction in our sample, albeit with a lower estimated odds ratio (OR) of 1.11 (P = 0.05, one-tailed). We genotyped this SNP (rs1884613) in an additional 4,400 subjects from North America and Poland. In this sample, the association was not confirmed and trended in the opposite direction (OR 0.88). Meta-analysis of our combined sample of 7,883 people (three times larger than the two initial reports combined) yielded an OR of 0.97 (P = 0.27). Finally, we provide an updated analysis of haplotype structure in the region to guide any further investigation of common variation in HNF4alpha. Although our combined results fail to replicate the previously reported association of common variants in HNF4alpha with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.
|
|
