Abstract
Science has come a long way with regard to the consideration of sex differences in clinical and preclinical research, but one field remains behind the curve: human statistical genetics. The goal of this commentary is to raise awareness and discussion about how to best consider and evaluate possible sex effects in the context of large-scale human genetic studies. Over the course of this commentary, we reinforce the importance of interpreting genetic results in the context of biological sex, establish evidence that sex differences are not being considered in human statistical genetics, and discuss how best to conduct and report such analyses. Our recommendation is to run stratified analyses by sex no matter the sample size or the result and report the findings. Summary statistics from stratified analyses are helpful for meta-analyses, and patterns of sex-dependent associations may be hidden in a combined dataset. In the age of declining sequencing costs, large consortia efforts, and a number of useful control samples, it is now time for the field of human genetics to appropriately include sex in the design, analysis, and reporting of results.
Highlights
In order to increase scientific rigor and reproducibility, Drs Collins (Director, NIH) and Clayton (Director, Office of Research on Women’s Health) spearheaded an effort to require preclinical scientists to consider sex differences in their research [1]
Over the course of this commentary, we hope to accomplish four goals: (1) identify why sex differences are important to consider in the context of genetics; (2) establish evidence that sex differences are not being considered in human genetics; (3) provide compelling counter-arguments to the traditional reasons given for not considering sex differences in genome-wide association studies (GWAS); and (4) offer suggestions on how to test for sex differences in analyses and why it is important to include and report these analyses, no matter the result
Inclusion of the term “Y-chromosome” yielded 63 articles from PubMed (0.19%) and 4 from Web of Science with ≥100 citations (0.13%). These search results are surprising; 1% of genetic association study publications in either PubMed or Web of Science report anything related to sex differences in their searchable text and an even smaller proportion consider the sex chromosomes
Summary
In order to increase scientific rigor and reproducibility, Drs Collins (Director, NIH) and Clayton (Director, Office of Research on Women’s Health) spearheaded an effort to require preclinical scientists to consider sex differences in their research [1]. The importance of considering sex in human genetic studies is not just limited to the realm of uncovering high-confidence associations between genotype and phenotype that would be hidden when sex is not considered.
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