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고려대학교

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Genome Med., Sep 27 2024, 16 (1) 114 | https://doi.org/10.1186/s13073-024-01385-6 Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism

Soo‑Whee Kim^1,2†, Hyeji Lee^1,2†, Da Yea Song^3,4, Gang‑Hee Lee^1,2, Jungeun Ji^1,2, Jung Woo Park⁵, Jae Hyun Han^3,6, Jee Won Lee⁷, Hee Jung Byun⁸, Ji Hyun Son⁸, Ye Rim Kim^3,4, Yoojeong Lee³, Jaewon Kim³, Ashish Jung⁹, Junehawk Lee⁵, Eunha Kim^10,11, So Hyun Kim¹², Jeong Ho Lee¹³, F. Kyle Satterstrom^14,15, Santhosh Girirajan¹⁶, Anders D. Børglum^17,18,19, Jakob Grove^17,18,19,20, Eunjoon Kim^21,22†, Donna M. Werling^23†, Hee Jeong Yoo^3,4†and Joon‑Yong An^1,2,9*†

¹Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea.

²L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, Republic of Korea.

³Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

⁴Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.

⁵Korea Institute of Science and Technology Information, Daejeon, Republic of Korea.

⁶Department of Psychiatry, College of Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea.

⁷Department of Psychiatry, Soonchunhyang University College of Medicine, Cheonan, South Korea.

⁸Department of Psychiatry, Seoul Metropolitan Children’s Hospital, Seoul, Republic of Korea.

⁹School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea.

¹⁰School of Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea.

¹¹BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea.

¹²Department of Psychology, Korea University, Seoul, Republic of Korea.

¹³Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

¹⁴Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

¹⁵Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

¹⁶Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA.

¹⁷The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

¹⁸Center for Genomics and Personalized Medicine, Aarhus, Denmark.

¹⁹Department of Biomedicine, Aarhus University, Aarhus, Denmark.

²⁰Bioinformatics Research Centre, BiRC, Aarhus University, Aarhus, Denmark.

²¹Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

²²Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea.

²³Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI, USA.

^†Soo-Whee Kim and Hyeji Lee contributed equally to this work.

^†Eunjoon Kim, Donna M. Werling, Hee Jeong Yoo and Joon-Yong An jointly supervised this work.

*Correspondence: Joon‑Yong An

Abstract

Whole-genome sequencing (WGS) analyses have found higher genetic burden in autistic females compared to males, supporting higher liability threshold in females. However, genomic evidence of sex differences has been limited to European ancestry to date and little is known about how genetic variation leads to autism-related traits within families across sex. To address this gap, we present WGS data of Korean autism families (n = 2255) and a Korean general population sample (n = 2500), the largest WGS data of East Asian ancestry. We analyzed sex differences in genetic burden and compared with cohorts of European ancestry (n = 15,839). Further, with extensively collected family-wise Korean autism phenotype data (n = 3730), we investigated sex differences in phenotypic scores and gene-phenotype associations within family. We observed robust female enrichment of de novo protein-truncating variants in autistic individuals across cohorts. However, sex differences in polygenic burden varied across cohorts and we found that the differential proportion of comorbid intellectual disability and severe autism symptoms mainly drove these variations. In siblings, males of autistic females exhibited the most severe social communication deficits. Female siblings exhibited lower phenotypic severity despite the higher polygenic burden than male siblings. Mothers also showed higher tolerance for polygenic burden than fathers, supporting higher liability threshold in females. Our findings indicate that genetic liability in autism is both sex- and phenotype-dependent, expanding the current understanding of autism's genetic complexity. Our work further suggests that family-based assessments of sex differences can help unravel underlying sex-differential liability in autism.

논문정보

형식Research article
게재일2024년 09월 (BRIC 등록일 2024-09-30)
연구진국내(교신)+국외 연구진
분야 의약학 > 유전 및 유전체의학

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