| 1. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 2. |
- Kato, Norihiro, et al.
(författare)
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Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
- 2015
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:11, s. 1282-1293
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
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| 3. |
- Mahajan, Anubha, et al.
(författare)
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Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.
- 2015
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
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| 4. |
- Müezzinler, Aysel, et al.
(författare)
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Smoking and All-cause Mortality in Older Adults : Results From the CHANCES Consortium
- 2015
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Ingår i: American Journal of Preventive Medicine. - : Elsevier BV. - 0749-3797 .- 1873-2607. ; 49:5, s. e53-e63
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Smoking is known to be a major cause of death among middle-aged adults, but evidence on its impact and the benefits of smoking cessation among older adults has remained limited. Therefore, we aimed to estimate the influence of smoking and smoking cessation on all-cause mortality in people aged ≥60 years.METHODS: Relative mortality and mortality rate advancement periods (RAPs) were estimated by Cox proportional hazards models for the population-based prospective cohort studies from Europe and the U.S. (CHANCES [Consortium on Health and Ageing: Network of Cohorts in Europe and the U.S.]), and subsequently pooled by individual participant meta-analysis. Statistical analyses were performed from June 2013 to March 2014.RESULTS: A total of 489,056 participants aged ≥60 years at baseline from 22 population-based cohort studies were included. Overall, 99,298 deaths were recorded. Current smokers had 2-fold and former smokers had 1.3-fold increased mortality compared with never smokers. These increases in mortality translated to RAPs of 6.4 (95% CI=4.8, 7.9) and 2.4 (95% CI=1.5, 3.4) years, respectively. A clear positive dose-response relationship was observed between number of currently smoked cigarettes and mortality. For former smokers, excess mortality and RAPs decreased with time since cessation, with RAPs of 3.9 (95% CI=3.0, 4.7), 2.7 (95% CI=1.8, 3.6), and 0.7 (95% CI=0.2, 1.1) for those who had quit <10, 10 to 19, and ≥20 years ago, respectively.CONCLUSIONS: Smoking remains as a strong risk factor for premature mortality in older individuals and cessation remains beneficial even at advanced ages. Efforts to support smoking abstinence at all ages should be a public health priority.
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| 5. |
- Warm, Katja, 1977-
(författare)
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The epidemiology of allergic sensitization and the relation to asthma and rhinitis
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Allergic sensitization is the most important risk factor for asthma and rhinitis among children, adolescents and young adults. Less is known about the incidence and remission of allergic sensitization, particularly in older adults. Furthermore, it is not clear if the earlier documented increase in prevalence of allergic sensitization continues. This thesis is focused on prevalence, incidence and remission of allergic sensitization to airborne allergens among adolescents and adults as well as on time trends in prevalence among adults. Furthermore, associated risk factors and the relation of allergic sensitization to asthma and rhinitis were assessed.Methods: In the study of children and adolescents, incidence, remission and prevalence of allergic sensitization were assessed in a cohort study of schoolchildren, aged 7-8 years (y) at baseline. In the studies of adults, incidence and remission of allergic sensitization were assessed in a randomly selected adult population sample in 1994 (n=664) aged 20-69 y, which was followed up in 2004 (n=555). Trends in prevalence of allergic sensitization were assessed by comparing two cross-sectional studies; the cohort from 1994 and another randomly selsected population sample examined in 2009 (n=737). The relation of allergic sensitization to asthma and rhinitis was determined in the adult cohort in 2009. Allergic sensitization was assessed by skin prick test (SPT) with ten common airborne allergens at ages 7-8, 11-12 and 19 y in the cohort of children and in the participants ≤ 60 y in the adult cohorts. Specific IgE to nine airborne allergens was analyzed in the adult cohorts in 2004 and 2009. Risk factors for allergic sensitization and variables defining respiratory disease and symptoms were assessed by questionnaires in the cohort of children and by structured interviews in the adult cohorts.Results: The 10-year cumulative incidence of allergic sensitization among the adults from 1994 to 2004 was 5%, while remission was 32%. In both adult cohorts, the prevalence of allergic sensitization was highest among young adults, aged 20-29 y, 55% and 61% and decreased significantly with increasing age. Among children and adolescents, both incidence and persistence of allergic sensitization were high, and the prevalence of allergic sensitization increased by age from 21% at age 7-8 y to 42% at age 19 y. Multisensitization at age 19 y was strongly associated with early onset of sensitization. The prevalence of sensitization to the major specific allergens birch, timothy, cat and dog as well as multisensitization (from 40% in 1994 to 56% in 2009, p=0.002) increased significantly from 1994 to 2009 among the adults. Sensitization to any allergen increased from 35% to 39%, however not significantly (p=0.13). A family history of allergic rhinitis was strongly and consistently associated with allergic sensitization in all ages. Male sex and urban living were significantly positively and birth order and furry animals at home in childhood were negatively associated with onset of sensitization before the age of 7-8 y, but not with onset of sensitization from 11-12y to 19 y. Young adult age and urban living were significant factors associated with allergic sensitization in adult age. Sensitization to any animal was significantly positively associated with current asthma (OR4.80 (95% CI 2.68-8.60)), whereas both sensitization to any pollen (OR 4.25 (2.55-7.06)) and any animal (OR 3.90 (95% CI 2.31-6.58)) were associated with current allergic rhinitis. The association between allergic sensitization and allergic rhinitis was strongest in young adult age and decreased with increasing age, while asthma was similarly associated with sensitization to any animal across all adult ages. Among asthmatics, the prevalence of allergic sensitization decreased with increasing age of asthma onset.Conclusion: Both incidence and persistence of allergic sensitization were high among children and adolescents explaining the increase in prevalence by increasing age. An inverse pattern with low incidence and high remission of allergic sensitization was seen among adults. The decrease in prevalence of allergic sensitization by increasing adult age might at least partly be explained by normal ageing and not only by an effect of year of birth (cohort effect). The significant increase in prevalence of sensitization to the specific allergens explained the significant increase in multisensitization over 15 years. A family history of allergy was the strongest and the only consistent risk factor for allergic sensitization in all ages. The prevalence of allergic sensitization decreased with increasing age of asthma onset among adult asthmatics.
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| 6. |
- Wessel, Jennifer, et al.
(författare)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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