Alkelai Anna, Greenbaum Lior, Docherty Anna R, Shabalin Andrey A, Povysil Gundula, Malakar Ayan, Hughes Daniel, Delaney Shannon L, Peabody Emma P, McNamara James, Gelfman Sahar, Baugh Evan H, Zoghbi Anthony W, Harms Matthew B, Hwang Hann-Shyan, Grossman-Jonish Anat, Aggarwal Vimla, Heinzen Erin L, Jobanputra Vaidehi, Pulver Ann E, Lerer Bernard, Goldstein David B
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA.
The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
Mol Psychiatry. 2022 Mar;27(3):1435-1447. doi: 10.1038/s41380-021-01383-9. Epub 2021 Nov 19.
Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N = 190), schizoaffective disorder (N = 49), or other conditions involving psychosis (N = 48). Participants were recruited in Israel and USA, mainly of Jewish, Arab, and other European ancestries. Trio (parents and proband) WGS was performed for 228 families (90.8%); in the other families, WGS included parents and at least two affected siblings. In the secondary analyses, we evaluated the contribution of rare variant enrichment in particular gene sets, and calculated polygenic risk score (PRS) for schizophrenia. For the primary outcome, diagnostic rate was 6.4%; we found clinically significant, single nucleotide variants (SNVs) or small insertions or deletions (indels) in 14 probands (5.6%), and copy number variants (CNVs) in 2 (0.8%). Significant enrichment of rare loss-of-function variants was observed in a gene set of top schizophrenia candidate genes in affected individuals, compared with population controls (N = 6,840). The PRS for schizophrenia was significantly increased in the affected individuals group, compared to their unaffected relatives. Last, we were also able to provide pharmacogenomics information based on CYP2D6 genotype data for most participants, and determine their antipsychotic metabolizer status. In conclusion, our findings suggest that WGS may have a role in the setting of both research and genetic counseling for individuals with schizophrenia and other psychotic disorders and their families.
精神分裂症具有多因素病因，涉及多基因结构。全基因组测序（WGS）在精神分裂症和其他精神障碍中的潜在益处尚未得到充分研究。我们调查了251个家系中临床WGS分析的结果，这些家系中的先证者被诊断为精神分裂症（N = 190）、分裂情感性障碍（N = 49）或其他涉及精神病的疾病（N = 48）。参与者招募自以色列和美国，主要为犹太、阿拉伯和其他欧洲血统。对228个家系（90.8%）进行了三联体（父母和先证者）WGS；在其他家系中，WGS包括父母和至少两个患病兄弟姐妹。在二次分析中，我们评估了特定基因集中罕见变异富集的贡献，并计算了精神分裂症的多基因风险评分（PRS）。对于主要结局，诊断率为6.4%；我们在14名先证者（5.6%）中发现了具有临床意义的单核苷酸变异（SNV）或小插入或缺失（indel），在2名先证者（0.8%）中发现了拷贝数变异（CNV）。与人群对照（N = 6840）相比，在受影响个体的顶级精神分裂症候选基因集中观察到罕见功能丧失变异的显著富集。与未受影响的亲属相比，受影响个体组的精神分裂症PRS显著升高。最后，我们还能够根据大多数参与者的CYP2D6基因型数据提供药物基因组学信息，并确定他们的抗精神病药物代谢状态。总之，我们的研究结果表明，WGS可能在精神分裂症和其他精神障碍患者及其家庭的研究和遗传咨询中发挥作用。
