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Sex-specific genetic architecture of human disease

Key Points

  • Nearly all human diseases are sexually dimorphic with respect to prevalence, age of onset, severity or disease course. Sex-specific differences in physiology, behaviour or anatomy might contribute to some of the differences in disease risk, but genetics also plays a part.

  • Gene expression patterns differ between males and females of all species examined, not only for genes on the sex chromosomes, but also for genes on the autosomes.

  • Genes with sex-biased gene expression evolve rapidly at the protein-coding level, whereas differences in gene regulation are often highly conserved.

  • Differences in gene expression between the sexes probably contribute to sexual dimorphism in disease risk and course.

  • Studies of disease-associated quantitative traits in humans suggest that many have a sex-specific genetic architecture, with estimates of heritability differing between males and females.

  • Genotype-by-sex interactions are common in model organisms, indicating that genotype-specific effects differ between males and females. Recent examples of genotype-by-sex interactions on disease risk suggest that such effects might be common in humans as well.

  • Genetic linkage and association studies that do not consider sex-specific genotype effects could miss a significant proportion of genes contributing to risk for complex diseases.

Abstract

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.

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Figure 1: Approximate mean sex-steroid levels in plasma in males and females.
Figure 2: Models of genotype–sex interactions reflecting genotype effects that differ between males and females.
Figure 3: Sex-specific prevalence rates, age of onset and sex ratios for common sex-skewed diseases.
Figure 4: Sex-specific heritabilities in males and females.
Figure 5: Strategy for discovering sex-specific eQTLs contributing to sexual dimorphism in disease risk.

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Acknowledgements

The authors are grateful to R. Rosenfield and J. L. Nelson for discussions, and to S. Khosla and E. Atkinson for providing primary data on sex-steroid levels in adults. The authors are supported in part by National Institutes of Health (NIH) grants HD021244, HL070831 and HL085197 (C.O.), GM077959 (Y.G.) and T32 HL07605 (D.A.L.). Y.G. is also supported by the Sloan foundation.

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Glossary

Heterogametic

Refers to the sex that produces gametes that have two different sex chromosomes. In mammals, males are the heterogametic sex (XY) and females are homogametic (XX), whereas in birds females are heterogametic (ZW).

Genetic architecture

Refers to the underlying genetic basis for a trait.

Pyloric stenosis

A common birth defect that results from the narrowing of the pylorus (lower part of the stomach), which prevents food and other stomach contents from passing into the intestine. This condition causes severe vomiting in infancy. Also called infantile hypertrophic pyloric stenosis.

Regulatory genome

The total set of different DNA molecules of an organelle, cell or organism that are involved in the regulation of gene expression.

Sexual selection

Differential reproductive success resulting from the competition for fertilization, which can occur through competition among the same sex (mate competition) or through attraction to the opposite sex (mate choice).

Ontogenetic conflict

Occurs when the same allele has different fitness consequences in juveniles and adults or in males and females.

Expression QTL

(eQTL). Loci at which genetic allelic variation is associated with variation in gene expression.

Alloimmune

An immune reaction against cells from another individual of the same species. Alloimmunity can occur during transfusion or transplantation, or during pregnancy.

Heritability

The proportion of the total phenotypic variance for a given trait that can be attributed to genetic variation among individuals.

Forced expiratory volume at 1 second

(FEV1). The volume exhaled in the first second of a forced expiratory manoeuvre. This index is used to assess airway obstruction, bronchoconstriction or bronchodilation.

Type I error

The probability of rejecting the null hypothesis when it is true, also referred to as a false positive.

Multiple testing

An analysis in which multiple independent hypotheses are tested. Multiple testing must be taken into account during statistical analysis, as the combined probability of type I error increases in an unadjusted analysis.

Consomic strain

Inbred strain in which a chromosome has been replaced by a homologous chromosome from another inbred strain.

Penetrance

The probability of observing a specific phenotype in individuals carrying a particular genotype.

Linkage disequilibrium

(LD). The nonrandom association of alleles at two or more loci. The pattern of linkage disequilibrium in a given genomic region reflects the history of natural selection, mutation, recombination, genetic drift, and other demographic and evolutionary forces.

Nondisjunction

The failure of chromosomes to separate at anaphase.

Aneuploidy

The presence of an abnormal number of chromosomes, either more or less than the diploid number.

Ectopic exchange

Homologous recombination between non-allelic chromosomal regions.

Odds ratio

(OR). Compares the likelihood of an outcome (for example, a disease) between two groups (for example, cases and controls). It is measured as the ratio of the odds in one group to the odds in the second group and can be calculated by the following formula: OR = p(1 − q)/q(1 − p), where p is the probability of the event occurring for the first group and q the probability for the second group.

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Ober, C., Loisel, D. & Gilad, Y. Sex-specific genetic architecture of human disease. Nat Rev Genet 9, 911–922 (2008). https://doi.org/10.1038/nrg2415

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