An integrated map of structural variation in 2,504 human genomes

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association. © 2015 Macmillan Publishers Limited. All rights reserved

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy.

Limited information is available on the effect of bisphosphonates in men receiving corticosteroid therapy. We studied 184 men among the patients enrolled in two, double-blind, placebo-controlled, 1-year studies with similar protocols. The studies evaluated the effects of risedronate in patients beginning corticosteroid treatment at a dose of at least 7.5 mg per day of prednisone or equivalent (prevention study) or continuing long-term treatment of corticosteroid at that dose (treatment study). The men received either placebo or risedronate (2.5 mg or 5 mg) daily, along with calcium supplementation (500-1000 mg). Endpoints included differences in bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter, assessment of vertebral fractures, changes in biochemical markers of bone turnover, and overall safety. In the treatment study, risedronate 5 mg significantly (P < 0.01) increased lumbar spine BMD by 4.8% at the lumbar spine, 2.1% at the femoral neck, and 2.6% at the femoral trochanter compared with baseline values. In the prevention study, bone loss was prevented with risedronate 5 mg; in the placebo group, BMD decreased significantly (P < 0.01) by 3.4%, 3.3%, and 3.4% in the lumbar spine, femoral neck, and trochanter, respectively, at 1 year. The differences between risedronate 5 mg and placebo groups were significant at all skeletal sites in the prevention study (P < 0.01) and at the lumbar spine in the treatment study (P < 0.001). The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than the 5 mg dose. When the data from the two studies were combined, the incidence of vertebral fractures decreased 82.4% (95% confidence interval, 36.6%-95.1%) in the pooled risedronate groups compared with placebo (P = 0.008). Risedronate was well tolerated in men, with a similar incidence of upper gastrointestinal adverse events in the placebo and treatment groups. Daily treatment with risedronate increases bone density and decreases vertebral fracture risk within 1 year in men receiving corticosteroid therapy

Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial

Summary: Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5 years were consistent with those seen at 3 years. Introduction: We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis. Methods: In the core study, healthy postmenopausal women with osteoporosis (N=7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40 mg were transitioned in a blinded manner to bazedoxifene 20 mg (bazedoxifene 40-/20-mg group) after 4 years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere. Results: A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium. Conclusion: Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5 years of therapy, consistent with findings at 3 years. © 2010 International Osteoporosis Foundation and National Osteoporosis Foundation

Prevention of bone loss with risedronate in glucocorticoid-treated rheumatoid arthritis patients

The aim of the study was to assess risedronate's effect on bone mineral density in postmenopausal women with rheumatoid arthritis receiving glucocorticoids. We carried out a two center, 2 year, double-masked, placebo-controlled trial with a third year of nontreatment follow-up. We studied 120 women requiring long-term glucocorticoid therapy at > 2.5 mg/day prednisolone randomized to treatment with daily placebo; daily 2.5 mg risedronate; or cyclical 15 mg risedronate (2 out of 12 weeks). At 97 weeks, bone mineral density was maintained at the lumbar spine (+1.4%) and trochanter (+0.4%) in the daily 2.5 mg risedronate group, while significant bone loss occurred in the placebo group (-1.6%, p = 0.03; and 4.0%, p &lt; 0.005, respectively). At the femoral neck, there was a nonsignificant bone loss in the daily 2.5 mg risedronate group (-1.0%) while in the placebo group bone mass decreased significantly (-3.6%, p &lt; 0.001). The difference between placebo and daily 2.5 mg risedronate groups was significant at the lumbar spine (p = 0.009) and trochanter (p = 0.02) but did not reach statistical significance at the femoral neck. Although not significantly different from placebo at the lumbar spine, the overall effect of the cyclical regimen was similar to that of the daily 2.5 mg risedronate regimen. Treatment withdrawal led to bone loss in the risedronate groups that was significant at the lumbar spine. A similar number of patients experienced adverse events (including upper gastrointestinal events) across treatment groups and risedronate was generally well tolerated. Thus risedronate preserves bone mass in postmenopausal women with rheumatoid arthritis receiving glucocorticoids while patients receiving a placebo have significant bone loss

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation. © 2016 Nature America, Inc. All rights reserved

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals

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 = 4.5×10−8- 1.2 ×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<3×10−4). 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 = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance