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Review
. 2023 Jun 1;110(6):903-912.
doi: 10.1016/j.ajhg.2023.04.009.

eXclusionarY: 10 years later, where are the sex chromosomes in GWASs?

Lei Sun  1 , Zhong Wang  2 , Tianyuan Lu  3 , Teri A Manolio  4 , Andrew D Paterson  5
Affiliations
Review

eXclusionarY: 10 years later, where are the sex chromosomes in GWASs?

Lei Sun et al. Am J Hum Genet. .

Abstract

10 years ago, a detailed analysis showed that only 33% of genome-wide association study (GWAS) results included the X chromosome. Multiple recommendations were made to combat such exclusion. Here, we re-surveyed the research landscape to determine whether these earlier recommendations had been translated. Unfortunately, among the genome-wide summary statistics reported in 2021 in the NHGRI-EBI GWAS Catalog, only 25% provided results for the X chromosome and 3% for the Y chromosome, suggesting that the exclusion phenomenon not only persists but has also expanded into an exclusionary problem. Normalizing by physical length of the chromosome, the average number of studies published through November 2022 with genome-wide-significant findings on the X chromosome is ∼1 study/Mb. By contrast, it ranges from ∼6 to ∼16 studies/Mb for chromosomes 4 and 19, respectively. Compared with the autosomal growth rate of ∼0.086 studies/Mb/year over the last decade, studies of the X chromosome grew at less than one-seventh that rate, only ∼0.012 studies/Mb/year. Among the studies that reported significant associations on the X chromosome, we noted extreme heterogeneities in data analysis and reporting of results, suggesting the need for clear guidelines. Unsurprisingly, among the 430 scores sampled from the PolyGenic Score Catalog, 0% contained weights for sex chromosomal SNPs. To overcome the dearth of sex chromosome analyses, we provide five sets of recommendations and future directions. Finally, until the sex chromosomes are included in a whole-genome study, instead of GWASs, we propose such studies would more properly be referred to as "AWASs," meaning "autosome-wide scans."

Keywords: GWAS; X chromosome; Y chromosome; data analysis; quality control; sex.

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Conflict of interest statement

Declaration of interests T.L. is an employee and shareholder of 5 Prime Sciences Inc.

Figures

Figure 1
Figure 1
Total number of studies and average number of studies per Mb reporting at least one genome-wide significant finding (p value < 5 × 10−8) stratified by chromosome, from the NHGRI-EBI GWAS Catalog (A and B) Total number of studies (A) and average number of studies (B). Genetic associations were indexed by unique PubMed IDs up to November 29, 2022. Studies reporting associations with multiple traits were only counted once.
Figure 2
Figure 2
Average number of studies per Mb reporting at least one genome-wide significant finding (p value < 5 × 10−8) over time, separately for the autosomes and X chromosome, from the NHGRI-EBI GWAS Catalog Genetic associations were indexed by unique PubMed IDs up to November 29, 2022. Studies reporting associations with multiple traits were only counted once.
Figure 3
Figure 3
Average number of studies per Mb reporting at least one genome-wide significant finding (p value < 5 × 10−8) per chromosome, from the NHGRI-EBI GWAS Catalog cumulatively, compared to chromosome-specific nucleotide diversity Genetic associations were indexed by unique PubMed IDs up to November 29, 2022. Studies reporting associations with multiple traits were only counted once. The solid slope was fitted using the autosomal data only, and the dashed curves are the 95% confidence bands.
See this image and copyright information in PMC

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