Abstract
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.
Highlights
Heritability is defined as the ratio of the genetic variance over the total variance of a trait [1], and can differ between the sexes for multiple reasons
In a classical paper from 1978, Eaves et al suggested that the key to detection of sex by genotype interactions lies with opposite-sex twin pairs who should be comparable in their similarity with dizygotic same-sex (DZss) twin pairs if a similar mechanism is accounting for the variation in the trait in males and females [2]
Evidence for sex-differences in the genetic architecture of complex human traits was found for 6 of the 122 variables
Summary
Heritability is defined as the ratio of the genetic variance over the total variance of a trait [1], and can differ between the sexes for multiple reasons. Different genes can be expressed in men and women, but even when the same genes are expressed in both sexes their relative importance can differ, and the environmental variance can vary, thereby changing the ratio of genetic over total variance. In a classical paper from 1978, Eaves et al suggested that the key to detection of sex by genotype interactions lies with opposite-sex twin pairs who should be comparable in their similarity with dizygotic same-sex (DZss) twin pairs if a similar mechanism is accounting for the variation in the trait in males and females [2]. Omission of unlike-sex pairs removes the most important tool for the early identification of sex-dependent mechanisms of determination.’’
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