Identification of rare genetic variants associated with schizophrenia has proven challenging due to multiple sources of heterogeneity, which may be reduced in founder populations. We examined ultra-rare exonic variants in 786 patients with schizophrenia and 463 healthy comparison subjects, all drawn from the Ashkenazi Jewish population. Cases had a higher frequency of novel missense or loss of function (MisLoF) variants compared to controls. Characterizing 141 "case-only" genes (in which 3 or more cases in our dataset had MisLoF variants with none found in controls), we identified cadherins as a novel gene set associated with schizophrenia, including a recurrent mutation in PCDHA3. Modeling the effects of purifying selection demonstrated that deleterious ultra-rare variants are greatly over-represented in the Ashkenazi population, resulting in enhanced power for rare variant association. Identification of cell adhesion genes in the cadherin/protocadherin family helps specify the synaptic abnormalities central to the disorder, and suggests novel potential treatment strategies.

中文翻译：

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在创始人人群中发现的新型超稀有外显子变体暗示着精神分裂症中的钙粘蛋白

由于多种来源的异质性，鉴定与精神分裂症相关的罕见遗传变异已被证明具有挑战性，而异质性的来源可能会在创始人群体中减少。我们检查了786名精神分裂症患者的超罕见外显子变异体和463名健康对照受试者，这些受试者均来自阿什肯纳齐犹太人口。与对照组相比，病例发生新的错义或功能丧失（MisLoF）变异的频率更高。我们鉴定了141个“仅病例”基因（在我们的数据集中有3个或更多病例具有MisLoF变异，而在对照中没有发现），我们将钙黏着蛋白鉴定为与精神分裂症相关的新型基因集，包括PCDHA3中的复发性突变。。对纯化选择的效果进行建模表明，有害的超稀有变种在Ashkenazi种群中被过度代表，从而增强了稀有变种关联的能力。钙粘蛋白/原钙粘蛋白家族中细胞粘附基因的鉴定有助于确定该疾病中心的突触异常，并提出新的潜在治疗策略。