Sex Differences In Genetic Architecture Research Articles

Genetic, Molecular, and Cellular Determinants of Sex-Specific Cardiovascular Traits.

Despite the well-known sex dimorphism in cardiovascular disease traits, the exact genetic, molecular, and cellular underpinnings of these differences are not well understood. A growing body of evidence currently points at the links between cardiovascular disease traits and the genome, epigenome, transcriptome, and metabolome. However, the sex-specific differences in these links remain largely unstudied due to challenges in bioinformatic methods, inadequate statistical power, analytic costs, and paucity of valid experimental models. This review article provides an overview of the literature on sex differences in genetic architecture, heritability, epigenetic changes, transcriptomic signatures, and metabolomic profiles in relation to cardiovascular disease traits. We also review the literature on the associations between sex hormones and cardiovascular disease traits and discuss the potential mechanisms underlying these associations, focusing on human studies.

Sex differences in genetic architecture in the UK Biobank.

Males and females present differences in complex traits and in the risk of a wide array of diseases. Genotype by sex (GxS) interactions are thought to account for some of these differences. However, the extent and basis of GxS are poorly understood. In the present study, we provide insights into both the scope and the mechanism of GxS across the genome of about 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits. We also found that, in some cases, sex-agnostic analyses may be missing trait-associated loci and looked into possible improvements in the prediction of high-level phenotypes. Finally, we studied the potential functional role of the differences observed through sex-biased gene expression and gene-level analyses. Our results suggest the need to consider sex-aware analyses for future studies to shed light onto possible sex-specific molecular mechanisms.

SA70 - SEX-STRATIFIED ANALYSIS OF OBSESSIVE-COMPULSIVE DISORDER REVEALS MINOR DIFFERENCES IN GENETIC ARCHITECTURE

Background Obsessive-Compulsive Disorder (OCD), a heritable neurobehavioral disorder, demonstrates sexual dimorphism in age of onset and clinical presentation, suggesting a possible sex difference in genetic architecture. Here, we present the first genome-wide assessment of sex-specific genetic architecture of OCD on currently the largest OCD cohort available from the Psychiatric Genomics Consortium (total cases and controls N=9,870 after quality control, 1:1.4 male/female ratio). Methods First, we performed a sex-stratified meta-GWAS to identify specific autosomal and sex chromosome genetic variants differentially associated to OCD risk in each of the sexes. Second, we assessed whether the most heterogeneous OCD risk alleles and top (p Results There were no genome-wide significant associations in either sex. Sex heterogenous SNPs (including and excluding SNPs in the HLA region) were strongly enriched for immune expression quantitative trait loci (p Discussion We present the first genome-wide assessment of sex-specific genetic architecture of OCD. We identified minor sex differences in genetic architecture of OCD, and although the sex-stratified sample size is likely too small to identify variants with small effect, we have developed a robust analytic pipeline for sex-stratified genetic analysis which will be applied in the near future to OCD as larger cohorts become available. The pipeline will also be applied to additional phenotypes where a sex bias in genetic effects may influence trait variation. This will enable a deeper understanding of how genetic variants may regulate biological processes influencing sex-biased phenotypes.

A genetic analysis of meat compositions in Japanese Black cattle: Genetic parameters and sex influence.

Meat composition in beef is related to eating quality and food functionality. Genetic parameters for several meat compositions including free amino acid, peptide and sugar, however, remain poorly described. In this study, we estimated genetic parameters for 51 meat components, including free amino acids, peptides, sugars and fatty acid compositions, and two carcase traits in 1,354 heifers and 1,797 steers of Japanese Black cattle. Heritability estimates were generally equivalent to or moderately greater than those in previous studies of this breed. Genetic correlations between free amino acids, peptides and sugars and carcase traits were often negative, suggesting a trade-off between traits. Using two-trait animal models that treat records from the two sexes as different traits, we estimated sex-specific heritabilities and cross-sex genetic correlations which indicate the sex differences in genetic architecture. In these analyses, 12 traits showed significant heritability differences between sexes and cross-sex genetic correlations occasionally deviated from unity. These results could be used to inform future breeding schemes and investigations of the genetic architecture of meat compositions in beef.

Sex Differences in Genetic Architecture of Complex Phenotypes?

We examined sex differences in familial resemblance for a broad range of behavioral, psychiatric and health related phenotypes (122 complex traits) in children and adults. There is a renewed interest in the importance of genotype by sex interaction in, for example, genome-wide association (GWA) studies of complex phenotypes. If different genes play a role across sex, GWA studies should consider the effect of genetic variants separately in men and women, which affects statistical power. Twin and family studies offer an opportunity to compare resemblance between opposite-sex family members to the resemblance between same-sex relatives, thereby presenting a test of quantitative and qualitative sex differences in the genetic architecture of complex traits. We analyzed data on lifestyle, personality, psychiatric disorder, health, growth, development and metabolic traits in dizygotic (DZ) same-sex and opposite-sex twins, as these siblings are perfectly matched for age and prenatal exposures. Sample size varied from slightly over 300 subjects for measures of brain function such as EEG power to over 30,000 subjects for childhood psychopathology and birth weight. For most phenotypes, sample sizes were large, with an average sample size of 9027 individuals. By testing whether the resemblance in DZ opposite-sex pairs is the same as in DZ same-sex pairs, we obtain evidence for genetic qualitative sex-differences in the genetic architecture of complex traits for 4% of phenotypes. We conclude that for most traits that were examined, the current evidence is that same the genes are operating in men and women.

Genetic Influences on Thought Problems in 7-Year-Olds: A Twin-Study of Genetic, Environmental and Rater Effects

The Thought-Problem scale (TP) of the CBCL assesses symptoms such as hallucinations and strange thoughts/behaviors and has been associated with other behavioral disorders. This study uses parental reports to examine the etiology of variation in TP, about which relatively little is known, in 7-year-old twins. Parental ratings on TP were collected in 8,962 7-year-old twin pairs. Because the distribution of TP scores was highly skewed scores were categorized into 3 classes. The data were analyzed under a threshold liability model with genetic structural equation modeling. Ratings from both parents were simultaneously analyzed to determine the rater agreement phenotype (or common phenotype [TPc]) and the rater specific phenotype [TPs] that represents rater disagreement caused by rater bias, measurement error and/or a unique view of the parents on the child's behavior. Scores on the TP-scale varied as a function of rater (fathers rated fewer problems), sex (boys scored higher) and zygosity (DZ twins scored higher). The TPc explained 67% of the total variance in the parental ratings. Variation in TPc was influenced mainly by the children's genotype (76%). Variance in TPs also showed a contribution of genetic factors (maternal reports: 61%, paternal reports: 65%), indicating that TPs does not only represent rater bias. Shared environmental influences were only found in the TPs. No sex differences in genetic architecture were observed. These results indicate an important contribution of genetic factors to thought problems in children as young as 7 years.

Heritability of Self-Reported Asthma and Allergy: A Study in Adult Dutch Twins, Siblings and Parents

The present study assessed the prevalence of asthma and allergy, and estimated the importance of genetic and environmental influences on asthma and allergy liability and their association. Longitudinal data on self-reported, doctor-diagnosed asthma and allergy were collected in over 14,000 individuals registered with the Netherlands Twin Register. Structural equation modeling was used for univariate and bivariate genetic analyses on data from twins, their siblings, and parents. Results showed no sex, age, and minimal birth cohort effects for asthma prevalence (11.8%). For allergy, prevalence was higher in women (19.8%) than in men (13.9%). Allergy prevalence at ages 22, 23, and 24 years increased from the 1970 to the 1980 birth cohort. The prevalence of allergy, but not of asthma, was higher in nontwin siblings than in twins. No assortative mating was observed. High (broad-sense) heritabilities were found for asthma (75%) and allergy (66%), with evidence for nonadditive genetic effects in asthma. The association between asthma and allergy (correlation=.65) was largely due to common genes (70%). No sex differences in genetic architecture were found. In conclusion, the prevalence of allergy but not of asthma increased in recent years. Individual differences in the liability to asthma, allergy and their co-occurrence are for a large part accounted for by differences in genetic background. Nonadditive gene action is important, which may have consequences for gene hunting strategies.

Genetic influences on fibrinogen, tissue plasminogen activatorantigen and von Willebrand factor in males and females

Differences in genetic influence on death from CHD between males and females have been reported. Haemostatic factors have consistently been associated with risk for coronary heart disease (CHD), but sex differences in genetic architecture have not been studied. This study in middle-aged twins investigates whether there are sex differences in means and in genetic and/or environmental variance components of haemostatic risk factors for CHD. A total of 93 monozygotic twin pairs (44 male and 49 female) and 116 dizygotic twin pairs (36 male, 40 female and 40 opposite sex) were available for this study. Structural equation modelling was used to estimate the relative influence of genetic and environmental factors on variation in levels of fibrinogen, tissue plasminogen activator (tPA) antigen and von Willebrand factor (vWF). Mean levels of tPA and vWF increased with age. Oral contraceptive pill (OCP) and menopause had significant influences on levels of fibrinogen and tPA. Genetic influences explained 39, 66 and 72% of the variation in levels of fibrinogen, tPA and vWF, respectively. No quantitative or qualitative differences of genetic influences on haemostatic levels were seen between males and females. Haemostatic factors may account for a significant part of the genetic risk for cardiovascular disease. No difference in genetic architecture for levels of fibrinogen, tPA or vWF was observed between males and females.

Sex differences and non-additivity in the effects of genes on personality.

New large-sample data show that non-additive genetic effects, probably epistatic interactions between loci, and sex-limited gene expression are significant features of the genetic architecture of human personality as measured by questionnaire scales of extraversion and neuroticism. Three large data sets--new data on large samples (n = 20,554) of US twins, their spouses, parents, siblings and children, correlations for Australian twins (n = 7,532), and previously published twin data from Finland (n = 14,288)--are subjected to an integrated analysis to test alternative hypotheses about the genetic causes of family resemblance in personality. When allowance is made for differences in reliability of the scales, the combined data are consistent with the same model for variation. There are significant amounts of genetic non-additivity for both dimensions of personality. The evidence favours additive x additive epistatic interactions rather than dominance. In the case of neuroticism, there is especially strong evidence of sex differences in genetic architecture favouring a greater relative contribution of non-additive genetic effects in males. The data confirm previous claims to find no major contribution of the shared environment of twins and siblings to these dimensions of personality. Correlations between spouses are zero, and the correlations for very large samples of siblings and non-identical twins do not differ significantly.

Sex differences and non-additivity in the effects of genes on personality

AbstractNew large-sample data show that non-additive genetic effects, probably epistatic interactions between loci, and sex-limited gene expression are significant features of the genetic architecture of human personality as measured by questionnaire scales of extraversion and neuroticism. Three large data sets – new data on large samples (n = 20 554) of US twins, their spouses, parents, siblings and children, correlations for Australian twins (n = 7 532), and previously published twin data from Finland (n = 14 288) – are subjected to an integrated analysis to test alternative hypotheses about the genetic causes of family resemblance in personality. When allowance is made for differences in reliability of the scales, the combined data are consistent with the same model for variation. There are significant amounts of genetic non-additivity for both dimensions of personality. The evidence favours additive × additive epistatic interactions rather than dominance. In the case of neuroticism, there is especially strong evidence of sex differences in genetic architecture favouring a greater relative contribution of non-additive genetic effects in males. The data confirm previous claims to find no major contribution of the shared environment of twins and siblings to these dimensions of personality. Correlations between spouses are zero, and the correlations for very large samples of siblings and non-identical twins do not differ significantly.

Quantitative genetic analysis of internalising and externalising problems in a large sample of 3-year-old twins.

For a quantitative genetic study of pre-school problem behaviours, we have collected data with the Child Behavior Checklist for 2 and 3-year-old children (CBCL 2/3). Questionnaires were completed by mothers of 3620 twin pairs: 633 monozygotic males, 581 dizygotic males, 695 monozygotic females, 519 dizygotic females and 1192 dizygotic opposite sex twin pairs. The genetic and environmental influences on the Externalising and Internalising Problem scales were estimated, simultaneously with sex differences and sibling interaction effects. Genetic factors explained most of the observed variance for both Externalising and Internalising Problems. Cooperative sibling interactions were found for Externalising Problems, indicating that twins reinforce each other's behaviour. Sex differences in genetic architecture were found for Externalising Problems. Genetic factors explained 75% of the variance in girls and 50% in boys. Shared environmental influences were only of importance in boys. For both problem scales, non-shared environmental factors accounted for 25 to 32% of the variance. The observed variances of Internalising Problems could be adequately explained by genetic and nonshared environmental factors, with genetic factors accounting for 68% of the variance.

Quantitative genetic analysis of Internalising and Externalising Problems in a large sample of 3-year-old twins

AbstractFor a quantitative genetic study of pre-school problem behaviours, we have collected data with the Child Behavior Checklist for 2 and 3-year-old children (CBCL 2/3). Questionnaires were completed by mothers of 3620 twin pairs: 633 monozygotic males, 581 dizygotic males, 695 monozygotic females, 519 dizygotic females and 1192 dizygotic opposite sex twin pairs. The genetic and environmental influences on the Externalising and Internalising Problem scales were estimated, simultaneously with sex differences and sibling interaction effects. Genetic factors explained most of the observed variance for both Externalising and Internalising Problems. Cooperative sibling interactions were found for Externalising Problems, indicating that twins reinforce each other's behaviour. Sex differences in genetic architecture were found for Externalising Problems. Genetic factors explained 75% of the variance in girls and 50% in boys. Shared environmental influences were only of importance in boys. For both problem scales, non-shared environmental factors accounted for 25 to 32% of the variance. The observed variances of Internalising Problems could be adequately explained by genetic and nonshared environmental factors, with genetic factors accounting for 68% of the variance.

Genetic and environmental influences on EEG coherence.

EEG coherence measures the covariation in electrical brain activity between two locations on the scalp and is used to study connectivity between cortical regions. The aim of this study was to determine the heritability of EEG coherence. Coherence was measured in a group of 213 16-yr-old twin pairs. By including male and female twin pairs in the sample, sex differences in genetic architecture were systematically examined. The EEG was obtained during quiet supine resting. Coherence was estimated for short and long distance combinations of electrode pairs along the anterior-posterior axis within a hemisphere for four frequency bands (delta, theta, alpha and beta). Averaged over all electrode combinations about 60% of the variance was explained by genetic factors for coherence in the theta, alpha and beta bands. For the delta band, the heritability was somewhat lower. No systematic sex differences in genetic architecture were found. All environmental influences were nonshared, i.e., unique factors including measurement error. Environmental factors shared by twin siblings did not influence variation in EEG coherence. These results suggest that individual differences in coherence form a potential candidate for (molecular) genetic studies on brain function.