Departments of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11550, USA; Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, NY 11004, USA; Institute for Behavioral Science, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA.
Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, NY 11004, USA; Institute for Behavioral Science, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA.
Neuron. 2021 May 5;109(9):1465-1478.e4. doi: 10.1016/j.neuron.2021.03.004. Epub 2021 Mar 22.
The identification of rare variants associated with schizophrenia has proven challenging due to genetic heterogeneity, which is reduced in founder populations. In samples from the Ashkenazi Jewish population, we report that schizophrenia cases had a greater frequency of novel missense or loss of function (MisLoF) ultra-rare variants (URVs) compared to controls, and the MisLoF URV burden was inversely correlated with polygenic risk scores in cases. Characterizing 141 "case-only" genes (MisLoF URVs in ≥3 cases with none in controls), the cadherin gene set was associated with schizophrenia. We report a recurrent case mutation in PCDHA3 that results in the formation of cytoplasmic aggregates and failure to engage in homophilic interactions on the plasma membrane in cultured cells. Modeling purifying selection, we demonstrate that deleterious URVs are greatly overrepresented in the Ashkenazi population, yielding enhanced power for association studies. Identification of the cadherin/protocadherin family as risk genes helps specify the synaptic abnormalities central to schizophrenia.
由于遗传异质性，与精神分裂症相关的罕见变异的鉴定一直具有挑战性，而在创始人群体中，这种遗传异质性会降低。在来自阿什肯纳兹犹太人群体的样本中，我们报告称，与对照组相比，精神分裂症病例中新型错义或功能丧失（MisLoF）超罕见变异（URV）的频率更高，并且病例中的 MisLoF URV 负担与多基因风险评分呈负相关。在 141 个“仅病例”基因（≥3 个病例中有 MisLoF URV，但对照组中没有）中，钙粘蛋白基因集与精神分裂症相关。我们报告了 PCDHA3 中的一个复发性病例突变，该突变导致细胞质聚集体的形成，并导致培养细胞中无法在质膜上进行同种型相互作用。通过对纯化选择进行建模，我们证明在阿什肯纳兹人群中，有害的 URV 大大过量，从而增强了关联研究的效力。钙粘蛋白/原钙粘蛋白家族作为风险基因的鉴定有助于确定与精神分裂症中心理失常相关的突触异常。
