Centre for Human Genetics, University of Marburg, Marburg, Germany.
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
Transl Psychiatry. 2020 Feb 4;10(1):57. doi: 10.1038/s41398-020-0732-y.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25-38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. WES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (p < 0.006) and schizophrenia (p = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.
双相情感障碍（BD）是一种高度遗传性的神经精神疾病，其特征是反复发作的抑郁和躁狂。研究表明，常见等位基因的累积影响解释了 25-38%的表型变异，而罕见变体可能导致 BD 的易感性。为了确定 BD 的罕见、高外显率的易感变体，对来自西班牙和德国的 27 个多受影响家族的每个家族中的 3 个受影响个体进行了全外显子组测序（WES）。WES 鉴定出 378 个罕见的、非同义的和潜在功能的变体。这些变体跨越 368 个基因，并且至少在一个家族中的所有三个受影响成员中都存在。368 个基因中有 8 个基因携带有罕见变体，这些变体至少涉及两个独立的家族。在一个涉及额外家族成员的扩展分离分析中，这 8 个基因中的 5 个基因携带的变体与 BD 完全或几乎完全共分离。其中包括在自闭症（p<0.006）和精神分裂症（p=0.015）的从头研究中报道的脑表达基因 RGS12 和 NCKAP5，这些基因被认为是最有前途的 BD 候选基因。对所有 368 个基因进行的基因富集分析显示，四个途径显著富集，包括在自闭症（p<0.006）和精神分裂症（p=0.015）的从头研究中报道的基因。这些结果表明，在罕见序列变异水平上，BD 与自闭症和精神分裂症之间可能存在遗传重叠。本研究提示了 BD 发病的新候选基因，并可能有助于更好地理解这种常见且常常严重的疾病的生物学基础。
