Contribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland
Contribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland
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DOI：
10.1038/s41467-018-08262-y
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发表时间：
2019-01-24
影响因子：
16.6
通讯作者：
Palotie, Aarno
中科院分区：
文献类型：
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作者：
Kurki, Mitja I.;Saarentaus, Elmo;Palotie, Aarno
新发变异在严重智力障碍 (ID) 中的作用已得到广泛研究，而轻度智力障碍的遗传学特征却较少。为了阐明轻度智力障碍的遗传学，我们研究了来自芬兰人群分离株的 442 名轻度智力障碍患者 (>50%)。通过外显子组测序，我们发现，严重 ID 基因 (27%) 中观察到已知 ID 基因中罕见的破坏性变异的频率明显高于轻度 ID (13%) 患者。我们进一步观察到尚未与 ID 相关的基因中功能变异的显着富集（OR：2.1）。我们发现，常见的变异多基因风险对 ID 有显着影响。由多基因风险评分解释的遗传力在轻度 ID 中教育程度 (EDU) 最高 (2.2%)，但在较严重 ID 中较低 (0.6%)。最后，我们在 CRADD ID 相关基因中鉴定出芬兰富集的纯合子变体。
The contribution of de novo variants in severe intellectual disability (ID) has been extensively studied whereas the genetics of mild ID has been less characterized. To elucidate the genetics of milder ID we studied 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. Using exome sequencing, we show that rare damaging variants in known ID genes are observed significantly more often in severe (27%) than in mild ID (13%) patients. We further observe a significant enrichment of functional variants in genes not yet associated with ID (OR: 2.1). We show that a common variant polygenic risk significantly contributes to ID. The heritability explained by polygenic risk score is the highest for educational attainment (EDU) in mild ID (2.2%) but lower for more severe ID (0.6%). Finally, we identify a Finland enriched homozygote variant in the CRADD ID associated gene.