eXclusionarY: Ten years later, where are the sex chromosomes in GWAS?

Abstract

SummaryTen years ago, a detailed analysis of genome-wide association studies showed that only 33% of the studies included the X chromosome. Multiple recommendations were made to combat eXclusion. Here we re-surveyed the research landscape to determine if these earlier recommendations had been translated. Unfortunately, among the 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 documented earlier not only persists but has also expanded into an eXclusionarY problem. Normalizing by physical length of the chromosome, the average number of studies published until 11/29/22 with genome-wide significant findings on the X chromosome is ~1 study/Mb. In 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 association on the X chromosome, there were extreme heterogeneities in how they analyzed the data and documented the results, suggesting the need for guidelines. Not surprisingly, 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 GWAS, we propose they be more properly referred to as “AWAS” for “autosome-wide scan”.