Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neurosurgery, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, New York, New York.
Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, New York, New York.
Biol Psychiatry. 2019 Jul 15;86(2):110-119. doi: 10.1016/j.biopsych.2018.12.009. Epub 2018 Dec 20.
Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.
Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.
CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.
CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
双相障碍 (BD) 的遗传风险是由许多常见等位基因引起的，而罕见的拷贝数变异 (CNVs) 的作用则不太清楚。BD 的亚型包括分裂情感性障碍双相型 (SAB)、双相 I 型障碍 (BD I) 和双相 II 型障碍 (BD II)，这些亚型根据精神病、躁狂和抑郁的突出程度和时间而有所不同。导致这些亚型症状组合的遗传因素了解甚少。
在 6353 例 BD 病例（3833 例 BD I [2676 例有精神病，850 例无精神病，307 例精神病史未知]、1436 例 BD II、579 例 SAB 和 505 例未特指的 BD）和 8656 例对照中分析罕见的大型 CNVs。使用 CNV 负担和精神分裂症多基因风险评分 (PRS) 来评估罕见和常见变异对 BD、BD 亚型和精神病风险的相对贡献。
当作为单一诊断实体处理时，BD 和对照之间的 CNV 负担没有差异。然而，SAB 的负担与对照（p =.001）、BD I（p =.0003）和 BD II（p =.0007）相比有所增加。SAB 的负担和精神分裂症 PRS 高于有精神病的 BD I（CNV p =.0007，PRS p =.004）和无精神病的 BD I（CNV p =.0004，PRS p = 3.9×10）。在 BD I 中，精神病与增加的精神分裂症 PRS 相关（p =.005），但与 CNV 负担无关。
BD 中的 CNV 负担仅限于 SAB。罕见和常见的遗传变异可能对精神病和其他类别的精神症状的风险有不同的贡献。
