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
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.
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.
Am J Hum Genet. 2025 Jan 2;112(1):135-153. doi: 10.1016/j.ajhg.2024.11.008. Epub 2024 Dec 19.
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 to 1.51 × 10), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on Xp22.2 (lead SNP rs12687599, p = 3.57 × 10) harboring ASB9/ASB11 and another encompassing DDX53 and the PTCHD1-AS long non-coding RNA (lead SNP rs5926125, p = 9.47 × 10). 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.
自闭症谱系障碍（ASD）在患病率上存在显著的男性偏向。对X染色体上罕见（<0.1）遗传变异的研究已表明超过20个基因与ASD发病机制有关，如MECP2、DDX3X和DMD。ASD中的“女性保护效应”表明，女性可能需要更高的遗传负荷才能表现出与男性相似的症状，但其机制尚不清楚。尽管基因组学技术取得了进展，但性染色体生物学性质的复杂性使得它们在全基因组研究中的代表性不足。在这里，我们利用来自自闭症之声MSSNG、西蒙斯单基因队列（SSC）和西蒙斯推动自闭症研究（SPARK）的6873名ASD患者（82%为男性）以及8981名人群对照（43%为男性）的全基因组测序数据进行了一项全X染色体关联研究（XWAS）。我们分析了418,652个X染色体变异，确定了59个与ASD相关的变异（p值为7.9×10至1.51×10），超过了Bonferroni校正阈值。主要发现包括Xp22.2上的显著区域（领先SNP rs12687599，p = 3.57×10）包含ASB9/ASB11，以及另一个包含DDX53和PTCHD1-AS长链非编码RNA的区域（领先SNP rs5926125，p = 9.47×10）。在对59个最显著相关SNP上下游10 kb范围内的基因进行定位时，发现了91个基因，其中17个与ASD相关（GRPR、AP1S2、DDX53、HDAC8、PCDH19、PTCHD1、PCDH11X、PTCHD1-AS、DMD、SYAP1、CNKSR2、GLRA2、OFD1、CDKL5、GPRASP2、NXF5和SH3KBP1）。FGF13成为一个X连锁的ASD候选基因，次要等位基因频率存在性别特异性差异突出了这一点。这些结果揭示了ASD中X染色体生物学的重要见解，确认并提名了有待进一步研究的基因和途径。
