Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.

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.

Contribution of genome-wide significant single-nucleotide polymorphisms and antiretroviral therapy to dyslipidemia in HIV-infected individuals: a longitudinal study.

BACKGROUND: HIV-infected individuals have an increased risk of myocardial infarction. Antiretroviral therapy (ART) is regarded as a major determinant of dyslipidemia in HIV-infected individuals. Previous genetic studies have been limited by the validity of the single-nucleotide polymorphisms (SNPs) interrogated and by cross-sectional design. Recent genome-wide association studies have reliably associated common SNPs to dyslipidemia in the general population. METHODS AND RESULTS: We validated the contribution of 42 SNPs (33 identified in genome-wide association studies and 9 previously reported SNPs not included in genome-wide association study chips) and of longitudinally measured key nongenetic variables (ART, underlying conditions, sex, age, ethnicity, and HIV disease parameters) to dyslipidemia in 745 HIV-infected study participants (n=34 565 lipid measurements; median follow-up, 7.6 years). The relative impact of SNPs and ART to lipid variation in the study population and their cumulative influence on sustained dyslipidemia at the level of the individual were calculated. SNPs were associated with lipid changes consistent with genome-wide association study estimates. SNPs explained up to 7.6% (non-high-density lipoprotein cholesterol), 6.2% (high-density lipoprotein cholesterol), and 6.8% (triglycerides) of lipid variation; ART explained 3.9% (non-high-density lipoprotein cholesterol), 1.5% (high-density lipoprotein cholesterol), and 6.2% (triglycerides). An individual with the most dyslipidemic antiretroviral and genetic background had an approximately 3- to 5-fold increased risk of sustained dyslipidemia compared with an individual with the least dyslipidemic therapy and genetic background. CONCLUSIONS: In the HIV-infected population treated with ART, the weight of the contribution of common SNPs and ART to dyslipidemia was similar. When selecting an ART regimen, genetic information should be considered in addition to the dyslipidemic effects of ART agents.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

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.

Polymorphisms in candidate genes and their association with carcass traits and meat quality in Nellore cattle

The objective of this work was to estimate the allele polymorphism frequencies of genes in Nellore cattle and associate them with meat quality and carcass traits. Six hundred males were genotyped for the following polymorphisms: DGAT1 (VNTR with 18 nucleotides at the promoter region); ANK1, a new polymorphism, identified and mapped here at the gene regulatory region NW_001494427.3; TCAP (AY428575.1:g.346G>A); and MYOG (NW_001501985:g.511G>C). In the association study, phenotype data of hot carcass weight, ribeye area, backfat thickness, percentage of intramuscular fat, shear force, myofibrillar fragmentation index, meat color (L*, a*, b*), and cooking losses were used. Allele B from the ANK1 gene was associated with greater redness (a*). Alleles 5R, 6R, and 7R from the DGAT1 VNTR gene were associated with increased intramuscular fat, reduced cooking losses and increased ribeye area, respectively. The single nucleotide polymorphism (SNP) of the TCAP gene was not polymorphic, and MYOG alleles were not associated with any of the evaluated characteristics. These results indicate that ANK1 and DGAT1 genes can be used in the selection of Nellore cattle for carcass and meat quality.

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 ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤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<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥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 provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Biological interpretation of genome-wide association studies using predicted gene functions.

The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.

Effect of race, genetic population structure, and genetic models in two-locus association studies: clustering of functional renin-angiotensin system gene variants in hypertension association studies

Previous genetic association studies have overlooked the potential for biased results when analyzing different population structures in ethnically diverse populations. The purpose of the present study was to quantify this bias in two-locus association studies conducted on an admixtured urban population. We studied the genetic structure distribution of angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensinogen methionine/threonine (M/T) polymorphisms in 382 subjects from three subgroups in a highly admixtured urban population. Group I included 150 white subjects; group II, 142 mulatto subjects, and group III, 90 black subjects. We conducted sample size simulation studies using these data in different genetic models of gene action and interaction and used genetic distance calculation algorithms to help determine the population structure for the studied loci. Our results showed a statistically different population structure distribution of both ACE I/D (P = 0.02, OR = 1.56, 95% CI = 1.05-2.33 for the D allele, white versus black subgroup) and angiotensinogen M/T polymorphism (P = 0.007, OR = 1.71, 95% CI = 1.14-2.58 for the T allele, white versus black subgroup). Different sample sizes are predicted to be determinant of the power to detect a given genotypic association with a particular phenotype when conducting two-locus association studies in admixtured populations. In addition, the postulated genetic model is also a major determinant of the power to detect any association in a given sample size. The present simulation study helped to demonstrate the complex interrelation among ethnicity, power of the association, and the postulated genetic model of action of a particular allele in the context of clustering studies. This information is essential for the correct planning and interpretation of future association studies conducted on this population.

Association of polymorphisms at the ADIPOR1 regulatory region with type 2 diabetes and body mass index in a Brazilian population with European or African ancestry

Association studies between ADIPOR1 genetic variants and predisposition to type 2 diabetes (DM2) have provided contradictory results. We determined if two single nucleotide polymorphisms (SNP c.-8503G>A and SNP c.10225C>G) in regulatory regions of ADIPOR1 in 567 Brazilian individuals of European (EA; N = 443) or African (AfA; N = 124) ancestry from rural (quilombo remnants; N = 439) and urban (N = 567) areas. We detected a significant effect of ethnicity on the distribution of the allelic frequencies of both SNPs in these populations (EA: -8503A = 0.27; AfA: -8503A = 0.16; P = 0.001 and EA: 10225G = 0.35; AfA: 10225G = 0.51; P < 0.001). Neither of the polymorphisms were associated with DM2 in the case-control study in EA (SNP c.-8503G>A: DM2 group -8503A = 0.26; control group -8503A = 0.30; P = 0.14/SNP 10225C>G: DM2 group 10225G = 0.37; control group 10225G = 0.32; P = 0.40) and AfA populations (SNP c.-8503G>A: DM2 group -8503A = 0.16; control group -8503A = 0.15; P = 0.34/SNP 10225C>G: DM2 group 10225G = 0.51; control group 10225G = 0.52; P = 0.50). Similarly, none of the polymorphisms were associated with metabolic/anthropometric risk factors for DM2 in any of the three populations, except for HDL cholesterol, which was significantly higher in AfA heterozygotes (GC = 53.75 ± 17.26 mg/dL) than in homozygotes. We conclude that ADIPOR1 polymorphisms are unlikely to be major risk factors for DM2 or for metabolic/anthropometric measurements that represent risk factors for DM2 in populations of European and African ancestries.

Genome-wide association analysis of feed intake and residual feed intake in Nellore cattle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Polymorphisms in candidate genes and their association with carcass traits and meat quality in Nellore cattle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Genome-wide association with residual body weight gain in Bos indicus cattle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Association between single-nucleotide polymorphisms and milk production traits in buffalo

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in buffaloes associated with milk yield and content, in addition to somatic cell scores based on the cross-species transferability of SNPs from cattle to buffalo. A total of 15,745 SNPs were analyzed, of which 1562 showed 1% significance and 4742 with 5% significance, which were associated for all traits studied. After application of Bonferroni's correction for multiple tests of the traits analyzed, we found 2 significant SNPs placed on cattle chromosomes BTA15 and BTA20, which are homologous to buffalo chromosomes BBU16 and BBU19, respectively. In this genome association study, we found several significant SNPs affecting buffalo milk production and quality. Furthermore, the use of the high-density bovine BeadChip was suitable for genomic analysis in buffaloes. Although extensive chromosome arm homology was described between cattle and buffalo, the exact chromosomal position of SNP markers associated with these economically important traits in buffalo can be determined only through buffalo genome sequencing.

Differentiation of African Components of Ancestry to Stratify Groups in a Case-Control Study of a Brazilian Urban Population

Background: Balancing the subject composition of case and control groups to create homogenous ancestries between each group is essential for medical association studies. Methods: We explored the applicability of single-tube 34-plex ancestry informative markers (AIM) single nucleotide polymorphisms (SNPs) to estimate the African Component of Ancestry (ACA) to design a future case-control association study of a Brazilian urban sample. Results: One hundred eighty individuals (107 case group; 73 control group) self-described as white, brown-intermediate or black were selected. The proportions of the relative contribution of a variable number of ancestral population components were similar between case and control groups. Moreover, the case and control groups demonstrated similar distributions for ACA <0.25 and >0.50 categories. Notably a high number of outlier values (23 samples) were observed among individuals with ACA <0.25. These individuals presented a high probability of Native American and East Asian ancestral components; however, no individuals originally giving these self-described ancestries were observed in this study. Conclusions: The strategy proposed for the assessment of ancestry and adjustment of case and control groups for an association study is an important step for the proper construction of the study, particularly when subjects are taken from a complex urban population. This can be achieved using a straight forward multiplexed AIM-SNPs assay of highly discriminatory ancestry markers.

Association between cannabis use and sexual risk behavior among young heterosexual adults

To study the association between cannabis use and frequent sexual risk behavior, we tested the hypothesis of a situational influence of cannabis use in sexual encounters using a combination of global association study and event-level analysis and examined possible mediator variables, including the personality trait of hedonism/risk preference, psychosocial stress, and HIV-related beliefs, using mediation models. The results of a computer-assisted telephone interview of a random sample of 2790 heterosexual men and women aged 16-24 years showed that risky sexual behavior was more frequent in cannabis-using men and women than in non-using persons. The results did not support a situational effect of cannabis intoxication on sexual risk behavior. The more frequent sexual risk behavior among cannabis users was mediated by decreased intentions to use HIV protection, by lower HIV-self-efficacy, and higher risk preference/hedonism. Only among women psychosocial stress was a partial mediator. The findings show that HIV prevention programs for cannabis-using young adults should emphasize the role of person variables instead of situation variables.