Chromosome X-wide common variant association study in autism spectrum disorder

Marla Mendes; Desmond Zeya Chen; Worrawat Engchuan; Thiago Peixoto Leal; Bhooma Thiruvahindrapuram; Brett Trost; Jennifer L Howe; Giovanna Pellecchia; Thomas Nalpathamkalam; Roumiana Alexandrova; Nelson Bautista Salazar; Ethan A McKee; Natalia Rivera-Alfaro; Meng-Chuan Lai; Sara Bandres-Ciga; Delnaz Roshandel; Clarrisa A Bradley; Evdokia Anagnostou; Lei Sun; Stephen W Scherer

doi:10.1016/j.ajhg.2024.11.008

Chromosome X-wide common variant association study in autism spectrum disorder

Am J Hum Genet. 2024 Dec 9:S0002-9297(24)00417-8. doi: 10.1016/j.ajhg.2024.11.008. Online ahead of print.

Authors

Marla Mendes¹, Desmond Zeya Chen², Worrawat Engchuan³, Thiago Peixoto Leal⁴, Bhooma Thiruvahindrapuram³, Brett Trost⁵, Jennifer L Howe³, Giovanna Pellecchia³, Thomas Nalpathamkalam³, Roumiana Alexandrova³, Nelson Bautista Salazar³, Ethan A McKee³, Natalia Rivera-Alfaro³, Meng-Chuan Lai⁶, Sara Bandres-Ciga⁷, Delnaz Roshandel³, Clarrisa A Bradley³, Evdokia Anagnostou⁸, Lei Sun⁹, Stephen W Scherer¹⁰

Affiliations

¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada. Electronic address: marla.mendesdeaquino@sickkids.ca.
² Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5S 3E3, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁴ Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, OH 44106, USA.
⁵ Molecular Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁶ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5G 2C1, Canada; Department of Psychiatry, The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5T 1R8, Canada.
⁷ Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Autism Research Centre, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁹ Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5S 3E3, Canada; Department of Statistical Sciences, Faculty of Arts and Science, University of Toronto, Toronto, ON M5G 1X6, Canada.
¹⁰ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: stephen.scherer@sickkids.ca.

PMID: 39706197
DOI: 10.1016/j.ajhg.2024.11.008

Abstract

Autism spectrum disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD. The "female protective effect" in ASD suggests that females may require a higher genetic burden to manifest symptoms similar to those in males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leaves them underrepresented in genome-wide studies. Here, we conducted an X-chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Collection (SSC), and Simons Powering Autism Research (SPARK), alongside 8,981 population controls (43% males). We analyzed 418,652 X chromosome variants, identifying 59 associated with ASD (p values 7.9 × 10^-6 to 1.51 × 10^-5), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on Xp22.2 (lead SNP rs12687599, p = 3.57 × 10^-7) harboring ASB9/ASB11 and another encompassing DDX53 and the PTCHD1-AS long non-coding RNA (lead SNP rs5926125, p = 9.47 × 10^-6). When mapping genes within 10 kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, and SH3KBP1). FGF13 emerged as an X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation.

Keywords: ASB9/ASB11; DMD; PTCHD1-AS/DDX53; X chromosome; XWAS; autism; common-rare variant association.