Why Does the X Chromosome Lag Behind Autosomes in GWAS Findings?

Overview

Journal PLoS Genet

Specialty Genetics

Date 2023 Feb 27

PMID 36848382

Authors

Ivan P Gorlov

Christopher I Amos

Affiliations

Soon will be listed here.

Abstract

The X-chromosome is among the largest human chromosomes. It differs from autosomes by a number of important features including hemizygosity in males, an almost complete inactivation of one copy in females, and unique patterns of recombination. We used data from the Catalog of Published Genome Wide Association Studies to compare densities of the GWAS-detected SNPs on the X-chromosome and autosomes. The density of GWAS-detected SNPs on the X-chromosome is 6-fold lower compared to the density of the GWAS-detected SNPs on autosomes. Differences between the X-chromosome and autosomes cannot be explained by differences in the overall SNP density, lower X-chromosome coverage by genotyping platforms or low call rate of X-chromosomal SNPs. Similar differences in the density of GWAS-detected SNPs were found in female-only GWASs (e.g. ovarian cancer GWASs). We hypothesized that the lower density of GWAS-detected SNPs on the X-chromosome compared to autosomes is not a result of a methodological bias, e.g. differences in coverage or call rates, but has a real underlying biological reason-a lower density of functional SNPs on the X-chromosome versus autosomes. This hypothesis is supported by the observation that (i) the overall SNP density of X-chromosome is lower compared to the SNP density on autosomes and that (ii) the density of genic SNPs on the X-chromosome is lower compared to autosomes while densities of intergenic SNPs are similar.

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References

Naj A . Genotype Imputation in Genome-Wide Association Studies. Curr Protoc Hum Genet. 2019; 102(1):e84. DOI: 10.1002/cphg.84. View

Webster T, Couse M, Grande B, Karlins E, Phung T, Richmond P . Identifying, understanding, and correcting technical artifacts on the sex chromosomes in next-generation sequencing data. Gigascience. 2019; 8(7). PMC: 6615978. DOI: 10.1093/gigascience/giz074. View

Wang Z, Sun L, Paterson A . Major sex differences in allele frequencies for X chromosomal variants in both the 1000 Genomes Project and gnomAD. PLoS Genet. 2022; 18(5):e1010231. PMC: 9187127. DOI: 10.1371/journal.pgen.1010231. View

Liang B, Ding H, Huang L, Luo H, Zhu X . GWAS in cancer: progress and challenges. Mol Genet Genomics. 2020; 295(3):537-561. DOI: 10.1007/s00438-020-01647-z. View

Chang D, Gao F, Slavney A, Ma L, Waldman Y, Sams A . Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases. PLoS One. 2014; 9(12):e113684. PMC: 4257614. DOI: 10.1371/journal.pone.0113684. View

Schurz H, Muller S, van Helden P, Tromp G, Hoal E, Kinnear C . Evaluating the Accuracy of Imputation Methods in a Five-Way Admixed Population. Front Genet. 2019; 10:34. PMC: 6370942. DOI: 10.3389/fgene.2019.00034. View

Keightley P . Rates and fitness consequences of new mutations in humans. Genetics. 2012; 190(2):295-304. PMC: 3276617. DOI: 10.1534/genetics.111.134668. View

Charlesworth D . When and how do sex-linked regions become sex chromosomes?. Evolution. 2021; 75(3):569-581. DOI: 10.1111/evo.14196. View

Smith E, Koller D, Panganiban C, Szelinger S, Zhang P, Badner J . Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes. PLoS Genet. 2011; 7(6):e1002134. PMC: 3128104. DOI: 10.1371/journal.pgen.1002134. View

10.

Schaffner S . The X chromosome in population genetics. Nat Rev Genet. 2004; 5(1):43-51. DOI: 10.1038/nrg1247. View

11.

Zivkovic D, Wiehe T . Second-order moments of segregating sites under variable population size. Genetics. 2008; 180(1):341-57. PMC: 2535686. DOI: 10.1534/genetics.108.091231. View

12.

Monteiro B, Arenas M, Prata M, Amorim A . Evolutionary dynamics of the human pseudoautosomal regions. PLoS Genet. 2021; 17(4):e1009532. PMC: 8084340. DOI: 10.1371/journal.pgen.1009532. View

13.

Visscher P, Brown M, McCarthy M, Yang J . Five years of GWAS discovery. Am J Hum Genet. 2012; 90(1):7-24. PMC: 3257326. DOI: 10.1016/j.ajhg.2011.11.029. View

14.

Byrska-Bishop M, Evani U, Zhao X, Basile A, Abel H, Regier A . High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios. Cell. 2022; 185(18):3426-3440.e19. PMC: 9439720. DOI: 10.1016/j.cell.2022.08.004. View

15.

Zhou W, Liu G, Hung R, Haycock P, Aldrich M, Andrew A . Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization. Int J Cancer. 2020; 148(5):1077-1086. PMC: 7845289. DOI: 10.1002/ijc.33292. View

16.

Panagiotou O, Willer C, Hirschhorn J, Ioannidis J . The power of meta-analysis in genome-wide association studies. Annu Rev Genomics Hum Genet. 2013; 14:441-65. PMC: 4040957. DOI: 10.1146/annurev-genom-091212-153520. View

17.

Pereira G, Doria S . X-chromosome inactivation: implications in human disease. J Genet. 2021; 100. View

18.

Zeggini E, Ioannidis J . Meta-analysis in genome-wide association studies. Pharmacogenomics. 2009; 10(2):191-201. PMC: 2695132. DOI: 10.2217/14622416.10.2.191. View

19.

Sherry S, Ward M, Kholodov M, Baker J, Phan L, Smigielski E . dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2000; 29(1):308-11. PMC: 29783. DOI: 10.1093/nar/29.1.308. View

20.

Kukurba K, Parsana P, Balliu B, Smith K, Zappala Z, Knowles D . Impact of the X Chromosome and sex on regulatory variation. Genome Res. 2016; 26(6):768-77. PMC: 4889977. DOI: 10.1101/gr.197897.115. View