PDF(Pubmed)
Abstract：
Schizophrenia and affective disorder are two major complex mental disorders with high heritability. Evidence shows that rare variants with significant clinical impacts contribute to the genetic liability of these two disorders. Also, rare variants associated with schizophrenia and affective disorders are highly personalized; each patient may carry different variants. We used whole genome sequencing analysis to study the genetic basis of two families with schizophrenia and major depressive disorder. We did not detect de novo, autosomal dominant, or recessive pathogenic or likely pathogenic variants associated with psychiatric disorders in these two families. Nevertheless, we identified multiple rare inherited variants with unknown significance in the probands. In family 1, with singleton schizophrenia, we detected four rare variants in genes implicated in schizophrenia, including p.Arg1627Trp of LAMA2, p.Pro1338Ser of CSMD1, p.Arg691Gly of TLR4, and Arg182X of AGTR2. The p.Arg691Gly of TLR4 was inherited from the father, while the other three were inherited from the mother. In family 2, with two affected sisters diagnosed with major depressive disorder, we detected three rare variants shared by the two sisters in three genes implicated in affective disorders, including p.Ala4551Gly of FAT1, p.Val231Leu of HOMER3, and p.Ile185Met of GPM6B. These three rare variants were assumed to be inherited from their parents. Prompted by these findings, we suggest that these rare inherited variants may interact with each other and lead to psychiatric conditions in these two families. Our observations support the conclusion that inherited rare variants may contribute to the heritability of psychiatric disorders.
摘要：
精神分裂症和情感障碍是两种主要的复杂精神障碍，具有很高的遗传性。证据表明，具有重大临床影响的罕见变异导致了这两种疾病的遗传倾向。此外，与精神分裂症和情感障碍相关的罕见变异是高度个性化的;每个患者可能携带不同的变异。我们使用全基因组测序分析来研究精神分裂症和重度抑郁症两个家庭的遗传基础。我们没有检测到从头，常染色体显性,或与这两个家庭中的精神疾病相关的隐性致病性或可能的致病性变异。然而，我们在先证者中发现了多个罕见的遗传变异,其意义未知.在家庭1中，患有单例精神分裂症，我们检测到四种与精神分裂症有关的罕见基因变异，包括LAMA2的p.Arg1627Trp、CSMD1的p.Pro1338Ser、TLR4的p.Arg691Gly和AGTR2的Arg182X。TLR4的p.Arg691Gly是从父亲那里继承的，而其他三个都是从母亲那里继承的。在家庭2中，有两个受影响的姐妹被诊断出患有重度抑郁症，我们在涉及情感障碍的三个基因中发现了两姐妹共有的三个罕见变异，包括FAT1的p.Ala4551Gly，HOMER3的p.Val231Leu和GPM6B的p.Ile185Met。假定这三个罕见的变体是从其父母遗传的。在这些发现的提示下，我们认为，这些罕见的遗传变异可能相互作用，并导致这两个家庭的精神病。我们的观察结果支持以下结论：遗传性罕见变异可能导致精神疾病的遗传性。
