The role of sex in the genomics of human complex traits

An Author Correction to this article was published on 28 June 2019

This article has been updated

Abstract

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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Fig. 1: Factors contributing to phenotypic sex differences.
Fig. 2: Epidemiological insights into sex-biased disease prevalence and heritability from biobank and insurance claims data.
Fig. 3: GWAS loci identified on autosomes and the X chromosome.

Change history

  • 28 June 2019

    In Box 4 of the originally published article, the text describing the Miami plot in part c of the figure contained some minor errors. Specifically, during pre-publication revision of the article, the authors updated the illustrative Miami plot (shown in figure part c) from that of reference 80 (Randall et al. PLoS Genet. (2013)) to a more recent study in reference 82 (Winkler et al. PLoS Genet. (2015)). The box text has now been updated to reflect that change. In paragraph 2, the trait has been updated from “hip circumference adjusted for body mass index” to “waist-to-hip ratio adjusted for body mass index (under 50 years old)” and it has been clarified that female GWAS data are shown on the top half of the plot with male data at the bottom. The original two citations of reference 80 in the Box 4 text have been updated to reference 82. Finally, a typographical artefact was corrected on the Y axis of the Miami plot, whereby the labels ‘14’ and ‘16’ in the top half of the plot we originally both shown as ‘12’. None of these corrections alter the overall illustrative point that genetic architectures for traits can differ between males and females, which was a conclusion of both reference 80 and reference 82.

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Acknowledgements

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.

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Nature Reviews Genetics thanks A. Keinan, K. Reue and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

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.

Heritability

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.

Imprinting

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.

Hemizygous

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.

Aneuploidy

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.

Interaction

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.

Pleiotropy

A phenomenon in which a single gene or genetic variant influences more than one phenotype.

Endophenotypes

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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