Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Hum Mol Genet. 2022 Nov 10;31(22):3769-3776. doi: 10.1093/hmg/ddac129.
Mental disorders present a global health concern and have limited treatment options. In today's medical practice, medications such as antidepressants are prescribed not only for depression but also for conditions such as anxiety and attention deficit hyperactivity disorder (ADHD). Therefore, identifying gene targets for specific disorders is important and offers improved precision. In this study, we performed a genetic analysis of six common mental disorders-ADHD, anxiety, depression, delays in mental development, intellectual disabilities (IDs) and speech/language disorder-in the ethnic minority of African Americans (AAs) using whole genome sequencing (WGS). WGS data were generated from blood-derived DNA from 4178 AA individuals, including 1384 patients with the diagnosis of at least one mental disorder. Mutation burden analysis was applied based on rare and deleterious mutations in the AA population between cases and controls, and further analyzed in the context of patients with single mental disorder diagnosis. Certain genes uncovered demonstrated significant P-values in mutation burden analysis. In addition, exclusive recurrences in specific type of disorder were scanned through gene-drug interaction databases to assess for availability of potential medications. We uncovered 15 genes harboring deleterious mutations, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) and Uronyl 2-Sulfotransferase (UST) for ADHD; Farnesyltransferase, CAAX Box, Beta (FNTB) for anxiety; Xin Actin Binding Repeat Containing 2 (XIRP2), Natriuretic Peptide C (NPPC), Serine/Threonine Kinase 33 (STK33), Pannexin 1 (PANX1) and Neurotensin (NTS) for depression; RUNX Family Transcription Factor 3 (RUNX3), Tachykinin Receptor 1 (TACR1) and NADH:Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) for delays in mental development; Hepsin (HPN) for ID and Collagen Type VI Alpha 3 Chain (COL6A3), Damage Specific DNA Binding Protein 1 (DDB1) and NADH:Ubiquinone Oxidoreductase Subunit A11 (NDUFA11) for speech/language disorder. Taken together, we have established critical insights into the development of new precision medicine approaches for mental disorders in AAs.
精神障碍是全球关注的健康问题，其治疗选择有限。在当今的医疗实践中，抗抑郁药等药物不仅用于治疗抑郁症，还用于治疗焦虑症和注意力缺陷多动障碍（ADHD）等疾病。因此，确定特定疾病的基因靶点很重要，可以提高精准度。在这项研究中，我们使用全基因组测序（WGS）对非裔美国人（AA）这一少数民族的六种常见精神障碍（ADHD、焦虑症、抑郁症、智力发育迟缓、智力残疾（IDs）和言语/语言障碍）进行了遗传分析。WGS 数据来自 4178 名 AA 个体的血液衍生 DNA，其中包括 1384 名至少患有一种精神障碍的患者。基于 AA 人群中病例和对照之间的罕见和有害突变，应用突变负担分析，并在单一精神障碍诊断患者的背景下进一步分析。通过基因-药物相互作用数据库扫描特定类型障碍的特有复发情况，评估潜在药物的可用性。我们发现了 15 个携带有害突变的基因，包括 3-羟-3-甲基戊二酰基辅酶 A 还原酶（HMGCR）和尿苷酰基 2-磺酸转移酶（UST）用于治疗 ADHD；法呢基转移酶，CAAX 盒，β（FNTB）用于焦虑症；XIRP2、NPPC、STK33、PANX1 和 NTS 用于抑郁症；RUNX 家族转录因子 3（RUNX3）、速激肽受体 1（TACR1）和 NADH：泛醌氧化还原酶核心亚单位 S7（NDUFS7）用于智力发育迟缓；Hepsin（HPN）用于 ID；COL6A3、DDB1 和 NDUFA11 用于言语/语言障碍。总之，我们为非裔美国人的精神障碍新的精准医疗方法的发展提供了重要的见解。
