Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Nature. 2018 Oct;562(7726):268-271. doi: 10.1038/s41586-018-0566-4. Epub 2018 Sep 26.
There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants. However, patients with the same genetic defect can have different clinical presentations, and some individuals who carry known disease-causing variants can appear unaffected. Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems. Although the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome-wide common variant burden by showing, in an independent sample of 728 trios (comprising a child plus both parents) from the same cohort, that this burden is over-transmitted from parents to children with neurodevelopmental disorders. Our common-variant signal is significantly positively correlated with genetic predisposition to lower educational attainment, decreased intelligence and risk of schizophrenia. We found that common-variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, which suggests that common-variant risk affects patients both with and without a monogenic diagnosis. In addition, previously published common-variant scores for autism, height, birth weight and intracranial volume were all correlated with these traits within our cohort, which suggests that phenotypic expression in individuals with monogenic disorders is affected by the same variants as in the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders that are typically considered to be monogenic.
有数千种罕见的人类疾病是由单一的有害、编码蛋白质的遗传变异引起的。然而，患有相同遗传缺陷的患者可能有不同的临床表现，而一些携带已知致病变异的个体可能看起来没有受到影响。在这里，为了了解是什么解释了这些差异，我们研究了一个由 6987 名儿童组成的队列，这些儿童被临床遗传学家评估为患有严重的神经发育障碍，如全面发育迟缓、自闭症，通常伴有其他器官系统的异常。尽管这些神经发育障碍的遗传原因预计几乎完全是单基因的，但我们表明，风险的 7.7%可归因于遗传性常见遗传变异。我们通过在来自同一队列的 728 个三体型（包含一个孩子和他的父母双方）的独立样本中复制了这种全基因组常见变体负担，表明这种负担从父母向患有神经发育障碍的孩子过度传递。我们的常见变体信号与遗传易感性呈显著正相关，易感性导致受教育程度降低、智力下降和精神分裂症风险增加。我们发现，在有和没有已知编码蛋白的诊断变异的个体之间，常见变体的风险没有显著差异，这表明常见变体的风险既影响有单基因诊断的患者，也影响没有单基因诊断的患者。此外，我们在队列中发现先前发表的与自闭症、身高、出生体重和颅内体积相关的常见变体评分与这些特征都呈正相关，这表明单基因疾病个体的表型表达受到与一般人群相同的变体的影响。我们的结果表明，常见遗传变异既影响神经发育障碍的总体风险，也影响其临床表现，而这些障碍通常被认为是单基因的。
