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

• Published in: American journal of human genetics Vol. 112; no. 1; pp. 135 - 153
• Main Authors: Mendes, Marla, Chen, Desmond Zeya, Engchuan, Worrawat, Leal, Thiago Peixoto, Thiruvahindrapuram, Bhooma, Trost, Brett, Howe, Jennifer L., Pellecchia, Giovanna, Nalpathamkalam, Thomas, Alexandrova, Roumiana, Salazar, Nelson Bautista, McKee, Ethan A., Rivera-Alfaro, Natalia, Lai, Meng-Chuan, Bandres-Ciga, Sara, Roshandel, Delnaz, Bradley, Clarrisa A., Anagnostou, Evdokia, Sun, Lei, Scherer, Stephen W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.01.2025; Elsevier
• Subjects: ASB9/ASB11; autism; Autism Spectrum Disorder - genetics; Chromosomes, Human, X - genetics; common-rare variant association; DMD; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Polymorphism, Single Nucleotide; PTCHD1-AS/DDX53; Whole Genome Sequencing; X chromosome; XWAS; PTCHD1-AS/DDX53; X chromosome; XWAS; DMD; common-rare variant association; autism; ASB9/ASB11
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2024.11.008

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. [Display omitted] An X-chromosome-wide association study of 6,873 individuals with autism identifies 59 variants and 17 genes associated with ASD, including DMD and PTCHD1-AS. The findings highlight sex-linked genetic influences and provide key insights into X-linked mechanisms underlying the male bias in ASD prevalence.