Nearly all human complex traits and disease phenotypes exhibit some degree of sex differences, including differences in prevalence, age of onset, severity or disease progression. Until recently, the underlying genetic mechanisms of such sex differences have been largely unexplored. Advances in genomic technologies and analytical approaches are now enabling a deeper investigation into the effect of sex on human health traits. In this Review, we discuss recent insights into the genetic models and mechanisms that lead to sex differences in complex traits. This knowledge is critical for developing deeper insight into the fundamental biology of sex differences and disease processes, thus facilitating precision medicine.
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The authors thank A. Rzhetsky and I. Mayzus for providing the prevalence of male and female traits from Truven MarketScan insurance claims data. The authors also thank A. Skol for helpful comments on the manuscript and M. Oliva for contributing to Figure1 and for providing NOD2 observations. This work was supported in part by US National Institutes of Health (NIH) grants 3P50MH094267-04S1, 1R01MH101820-S1 and HG007598-S1.
Nature Reviews Genetics thanks A. Keinan, K. Reue and the other, anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Sex differences
Significant differences in the means of a phenotype between males and females — also includes sexual dimorphism.
- Genetic liability
The total contribution of the risk or trait-influencing alleles for a given trait.
- Sexual dimorphism
Two distinct forms of a trait that differentiate members of the same species by their sex.
The proportion of the total phenotypic variance in a population that can be attributed to genetic variance in the population.
- Genetic architecture
The number, allele frequency and effect size of genetic variants that influence a trait.
- Pseudoautosomal regions
(PARs). Homologous regions on the X and Y chromosomes that recombine and are not inherited in a sex-dependent manner.
An epigenetic mechanism of transcriptional silencing of a gene in a gamete inherited from the mother or the father, leading to a parent-of-origin specific imbalance in gene expression of the two inherited copies.
- Dosage compensation
A process by which gene expression is balanced between two members of the same species (typically between two biological sexes). In humans, this is accomplished by silencing of one of the copies of the X chromosome in females.
A haploid zygosity state in which only one copy of a gene is present, such as Y chromosome genes, which do not recombine with the X chromosome
- X chromosome inactivation
(XCI). A process by which one of the copies of an X chromosome is silenced in each female cell through epigenetic modification, such as DNA methylation.
- Sex-biased gene expression
A term that encompasses various gene regulatory phenomena that may differ between sexes, including differential expression and differential splicing.
Abnormal number of chromosomes in a cell.
- Total liability
The combination of genetic and environmental factors that contribute to the development of a complex trait.
- Missing heritability
The observation that for most complex traits, the sum of the identified trait-associated genetic variation contributes only a proportion of the estimated trait heritability.
- Sexually differentiated
(Also known as sex-specific or sex-biased). A term used to describe a phenotype exhibiting a quantitative or qualitative sex difference.
- ChrY haplogroups
Groups of haplotypes that map to the same common ancestor on the patriline.
A phenomenon in which the effect of one variable depends on the value of another variable (for example, gene-by-environment interaction).
- Type II error
A false negative finding, that is, a failure to reject a false null hypothesis.
- Copy number variants
(CNVs). Regions of the genome that may be duplicated or deleted and for which the number of copies vary between individuals.
- Sexually antagonistic selection
A situation in which selection on an allele acts in opposite directions in males and females because opposite phenotypes associated with the allele are optimal in each sex.
- Genetic correlation
An estimate of the proportion of genetic variance shared by two traits, measured from 0 to 1, with 1 indicating complete genetic correlation.
- Anthropometric traits
Physical properties of the human body including but not limited to secondary sex characteristics such as height, waist and hip measurements.
A phenomenon in which a single gene or genetic variant influences more than one phenotype.
Intermediate measurable phenotypes between an individual’s genotype and a phenotype, for example, characteristics of the transcriptome.
- Sex differentially expressed
(sex-DE). A situation in which mean mRNA levels of a gene differ between tissues or cells derived from males or females.
- Hormone response elements
Short segments of DNA in gene promoters to which hormone receptor complexes bind and regulate gene expression.
- Sex-biased splicing
A situation in which different transcript splicing isoforms (or different ratios of them) are present in tissues or cells derived from males or females.
- Expression quantitative trait loci
(eQTLs). Regions of the genome containing genetic variants associated with gene expression levels in a given tissue or cell type.
- Sex-biased eQTLs
Expression quantitative trait loci (eQTLs) at which the allelic effect size differs between females and males.
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Khramtsova, E.A., Davis, L.K. & Stranger, B.E. The role of sex in the genomics of human complex traits. Nat Rev Genet 20, 173–190 (2019). https://doi.org/10.1038/s41576-018-0083-1
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