Chromosome X-Wide Common Variant Association Study (XWAS) in Autism Spectrum Disorder.

Autor:	Mendes M; 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., Chen DZ; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.; Department of Statistical Sciences, Faculty of Arts and Science, University of Toronto, Toronto, ON, M5G 1X6, Canada., Engchuan W; 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., Leal TP; Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, OH, 44106, USA., Thiruvahindrapuram B; 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., Trost B; 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., Howe JL; 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., Pellecchia G; 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., Nalpathamkalam T; 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., Alexandrova R; 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., Salazar NB; 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., McKee EA; 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., Alfaro NR; 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., Lai MC; 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., Bandres-Ciga S; Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, 20892, USA., Roshandel D; 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., Bradley CA; 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., Anagnostou E; 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., Sun L; Department of Statistical Sciences, Faculty of Arts and Science, University of Toronto, Toronto, ON, M5G 1X6, Canada.; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5S 3E3, Canada., Scherer SW; 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.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Jul 18. Date of Electronic Publication: 2024 Jul 18.
DOI:	10.1101/2024.07.18.24310640
Abstrakt:	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 similar symptoms as males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leave 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 Cohort SSC, and Simons Foundation 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 chrXp22.2 (lead SNP=rs12687599, p=3.57×10 -7 ) harboring ASB9 / ASB11 , and another encompassing DDX53/PTCHD1-AS long non-coding RNA (lead SNP=rs5926125, p=9.47×10 -6 ). When mapping genes within 10kb 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 , SH3KBP1 ). FGF13 emerged as a novel X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant new insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation. Competing Interests: At the time of this study and its publication, S.W.S. served on the Scientific Advisory Committee of Population Bio. Intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations.
Databáze:	MEDLINE
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