| 1. |
- Palmer, Nicholette D, et al.
(författare)
-
A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
-
Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
-
Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
|
|
| 2. |
- Speliotes, Elizabeth K., et al.
(författare)
-
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
|
|
| 3. |
- Heid, Iris M, et al.
(författare)
-
Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
-
Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
|
|
| 4. |
- Horikoshi, Momoko, et al.
(författare)
-
New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:1
-
Tidskriftsartikel (refereegranskat)abstract
- Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
|
|
| 5. |
- Scott, Robert A., et al.
(författare)
-
Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
-
Tidskriftsartikel (refereegranskat)abstract
- Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
|
|
| 6. |
- Barker, Adam, et al.
(författare)
-
Association of genetic loci with glucose levels in childhood and adolescence a meta-analysis of over 6,000 children
- 2011
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 60:6, s. 1805-1812
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS-A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS-Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level of 0.026 mrnol/L (0.021-0.031) for each unit increase in the score. CONCLUSIONS-Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011
|
|
| 7. |
- Taal, H. Rob, et al.
(författare)
-
Common variants at 12q15 and 12q24 are associated with infant head circumference
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 532-538
-
Tidskriftsartikel (refereegranskat)abstract
- To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
|
|
| 8. |
- Dastani, Zari, et al.
(författare)
-
Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals
- 2012
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002607-
-
Tidskriftsartikel (refereegranskat)abstract
- Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P=4.5 x 10(-8)-1.2 x 10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3 x 10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p=4.3 x 10(-3), n = 22,044), increased triglycerides (p=2.6 x 10(-14), n = 93,440), increased waist-to-hip ratio (p=1.8 x 10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p=4.4 x 10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p=4.5x10(-13), n = 96,748) and decreased BMI (p= 1.4 x 10(-14), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
|
|
| 9. |
- Kilpeläinen, Tuomas O, et al.
(författare)
-
Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.
- 2011
-
Ingår i: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 8:11
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). METHODS AND FINDINGS: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. CONCLUSIONS: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
|
|
| 10. |
- Lind, Lars, et al.
(författare)
-
Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin.
- 2014
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:7
-
Tidskriftsartikel (refereegranskat)abstract
- Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
|
|
