Majority of human traits do not show evidence for sex-specific genetic and environmental effects.
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ABSTRACT:
SUBMITTER: Stringer S
PROVIDER: S-EPMC5561094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Sex differences have been shown in laboratory biomarkers; however, the extent to which this is due to genetics is unknown. In this study, we infer sex-specific genetic parameters (heritability and genetic correlation) across 33 quantitative biomarker traits in 181,064 females and 156,135 males from the UK Biobank study. We apply a Bayesian Mixture Model, Sex Effects Mixture Model (SEMM), to Genome-wide Association Study summary statistics in order to (1) estimate the contributions of sex to the genetic variance of these biomarkers and (2) identify variants whose statistical association with these traits is sex-specific. We find that the genetics of most biomarker traits are shared between males and females, with the notable exception of testosterone, where we identify 119 female and 445 male-specific variants. These include protein-altering variants in steroid hormone production genes (POR, UGT2B7). Using the sex-specific variants as genetic instruments for Mendelian randomization, we find evidence for causal links between testosterone levels and height, body mass index, waist and hip circumference, and type 2 diabetes. We also show that sex-specific polygenic risk score models for testosterone outperform a combined model. Overall, these results demonstrate that while sex has a limited role in the genetics of most biomarker traits, sex plays an important role in testosterone genetics.
| S-EPMC7794464 | biostudies-literature
Project description:BackgroundThe origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.MethodsUsing European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (rg < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations.ResultsWe observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior).ConclusionsSex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.
| S-EPMC8163257 | biostudies-literature
Project description:Parkinson's disease is an age-related neurodegenerative disorder with a higher incidence in males than females. The causes for this sex difference are unknown. Genome-wide association studies (GWAS) have identified 90 Parkinson's disease risk loci, but the genetic studies have not found sex-specific differences in allele frequency on autosomal chromosomes or sex chromosomes. Genetic variants, however, could exert sex-specific effects on gene function and regulation of gene expression. To identify genetic loci that might have sex-specific effects, we studied pleiotropy between Parkinson's disease and sex-specific traits. Summary statistics from GWASs were acquired from large-scale consortia for Parkinson's disease (n cases = 13 708; n controls = 95 282), age at menarche (n = 368 888 females) and age at menopause (n = 69 360 females). We applied the conditional/conjunctional false discovery rate (FDR) method to identify shared loci between Parkinson's disease and these sex-specific traits. Next, we investigated sex-specific gene expression differences in the superior frontal cortex of both neuropathologically healthy individuals and Parkinson's disease patients (n cases = 61; n controls = 23). To provide biological insights to the genetic pleiotropy, we performed sex-specific expression quantitative trait locus (eQTL) analysis and sex-specific age-related differential expression analysis for genes mapped to Parkinson's disease risk loci. Through conditional/conjunctional FDR analysis we found 11 loci shared between Parkinson's disease and the sex-specific traits age at menarche and age at menopause. Gene-set and pathway analysis of the genes mapped to these loci highlighted the importance of the immune response in determining an increased disease incidence in the male population. Moreover, we highlighted a total of nine genes whose expression or age-related expression in the human brain is influenced by genetic variants in a sex-specific manner. With these analyses we demonstrated that the lack of clear sex-specific differences in allele frequencies for Parkinson's disease loci does not exclude a genetic contribution to differences in disease incidence. Moreover, further studies are needed to elucidate the role that the candidate genes identified here could have in determining a higher incidence of Parkinson's disease in the male population.
| S-EPMC10907091 | biostudies-literature
Project description:Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.
| S-EPMC2694620 | biostudies-literature
Project description:Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
| S-EPMC3674993 | biostudies-literature
Project description:ObjectiveAtherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid intima-media thickness (cIMT) can be used to measure vascular remodeling, which is indicative of atherosclerosis. Genome-wide association studies have identified many genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here, we conducted genome-wide association analyses in UKB (UK Biobank; N=22 179), the largest single study with consistent cIMT measurements. Approach and Results: We used BOLT-LMM software to run linear regression of cIMT in UKB, adjusted for age, sex, and genotyping chip. In white British participants, we identified 5 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a locus on chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body mass index and glucometabolic traits were also observed. Two loci influenced risk of ischemic heart disease.ConclusionsThese findings replicate previously reported associations, highlight novel biology, and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.
| S-EPMC6975521 | biostudies-literature
Project description:Dispersal in most group-living species ensures gene flow among groups, but in cooperative social spiders, juvenile dispersal is suppressed and colonies are highly inbred. It has been suggested that such inbred sociality is advantageous in the short term, but likely to lead to extinction or reduced speciation rates in the long run. In this situation, very low levels of dispersal and gene flow among colonies may have unusually important impacts on fitness and persistence of social spiders. We investigated sex-specific differences in dispersal and gene flow among colonies, as reflected in the genetic structure within colonies and populations of the African social spider Stegodyphus dumicola Pocock, 1898 (Eresidae). We used DNA fingerprinting and mtDNA sequence data along with spatial mapping of colonies to compare male and female patterns of relatedness within and among colonies at three study sites. Samples were collected during and shortly after the mating season to detect sex-specific dispersal. Distribution of mtDNA haplotypes was consistent with proliferation of social nests by budding and medium- to long-distance dispersal by ballooning females. Analysis of molecular variance and spatial autocorrelation analyses of AFLPs showed high levels of genetic similarity within colonies, and STRUCTURE analyses revealed that the number of source populations contributing to colonies ranged from one to three. We also showed significant evidence of male dispersal among colonies at one site. These results support the hypothesis that in social spiders, genetic cohesion among populations is maintained by long-distance dispersal of female colony founders. Genetic diversity within colonies is maintained by colony initiation by multiple dispersing females, and adult male dispersal over short distances. Male dispersal may be particularly important in maintaining gene flow among colonies in local populations.
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Project description:Effective immunity requires a complex network of cellular and humoral components that interact with each other and are influenced by different environmental and host factors. We used a systems biology approach to comprehensively assess the impact of environmental and genetic factors on immune cell populations in peripheral blood, including associations with immunoglobulin concentrations, from ∼500 healthy volunteers from the Human Functional Genomics Project. Genetic heritability estimation showed that variations in T cell numbers are more strongly driven by genetic factors, while B cell counts are more environmentally influenced. Quantitative trait loci (QTL) mapping identified eight independent genomic loci associated with leukocyte count variation, including four associations with T and B cell subtypes. The QTLs identified were enriched among genome-wide association study (GWAS) SNPs reported to increase susceptibility to immune-mediated diseases. Our systems approach provides insights into cellular and humoral immune trait variability in humans.
| S-EPMC5130901 | biostudies-literature
Project description:Serum sodium concentration is the clinical index of systemic water balance. Although disordered water balance is common and morbid, little is known about genetic effects on serum sodium concentration at the population level. Prior studies addressed only participants of European descent and either failed to demonstrate significant heritability or showed only modest effect. We investigated heritability of serum sodium concentration in large cohorts reflecting a range of races/ethnicities, including the Framingham Heart Study (FHS, non-Hispanic Caucasian), the Heredity and Phenotype Intervention Heart Study (HAPI, Amish Caucasian), the Jackson Heart Study (JHS, African American), the Strong Heart Family Study (SHFS, American Indian), and the Genetics of Kidney Disease in Zuni Indians Study (GKDZI, American Indian). Serum sodium was transformed for the osmotic effect of glucose, and participants with markedly elevated glucose or reduced estimated glomerular filtration rate (eGFR) were excluded. Using a standard variance components method, incorporating covariates of age, glucose, and eGFR, we found heritability to be high in African American and American Indian populations and much more modest in non-Hispanic Caucasian populations. Estimates among females increased after stratification on sex and were suggestive among female participants in FHS (0.18 ± 0.12, P = 0.057) and male participants in JHS (0.24 ± 0.16, P = 0.067) and statistically significant among female participants in JHS (0.44 ± 0.09, P = 1 × 10 ??), SHFS (0.59 ± 0.05, P = 9.4 × 10???), and GKDZI (0.46 ± 0.15, P = 1.7 × 10??), and male participants in HAPI (0.18 ± 0.12, P = 0.03) and SHFS (0.67 ± 0.07, P = 5.4 × 10?²?). Exclusion of diuretic users increased heritability among females and was significant in all cohorts where data were available. In aggregate, these data strongly support the heritability of systemic water balance and underscore sex and ethnicity-specific effects.
| S-EPMC3289114 | biostudies-literature
Project description:Animals searching for food and sexual partners often use odourant mixtures combining food-derived molecules and pheromones. For orientation, the vinegar fly Drosophila melanogaster uses three types of chemical cues: (i) the male volatile pheromone 11-cis-vaccenyl acetate (cVA), (ii) sex-specific cuticular hydrocarbons (CHs; and CH-derived compounds), and (iii) food-derived molecules resulting from microbiota activity. To evaluate the effects of these chemicals on odour-tracking behaviour, we tested Drosophila individuals in a wind tunnel. Upwind flight and food preference were measured in individual control males and females presented with a choice of two food sources labelled by fly lines producing varying amounts of CHs and/or cVA. The flies originated from different species or strains, or their microbiota was manipulated. We found that (i) fly-labelled food could attract-but never repel-flies; (ii) the landing frequency on fly-labelled food was positively correlated with an increased flight duration; (iii) male-but not female or non-sex-specific-CHs tended to increase the landing frequency on fly-labelled food; (iv) cVA increased female-but not male-preference for cVA-rich food; and (v) microbiota-derived compounds only affected male upwind flight latency. Therefore, sex pheromones interact with food volatile chemicals to induce sex-specific flight responses in Drosophila.
| S-EPMC6802089 | biostudies-other