We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R = 0.32–0.38, p < 10⁻¹²⁶). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient = 0.14, p = 3.38 × 10⁻⁴). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R = 0.24–0.68, p < 0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R = 0.09–0.22, p < 10⁻⁹²). Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of “genetic anticipation” in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R = 0.05–0.26, p < 0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.

我们检查了来自四个神经发育疾病队列和英国生物银行的 97,000 多个家庭，以确定父母中导致儿童神经发育疾病风险的表型和遗传模式。我们确定了父母和孩子的六种表型之间的疾病内和跨疾病相关性，例如强迫症（R = 0.32–0.38，p < 10 ⁻¹²⁶ ）。我们还发现，父母亚临床自闭症特征的测量与儿童自闭症严重程度的测量相关，包括双亲平均社会反应量表分数和先证者重复行为量表分数（回归系数 = 0.14，p = 3.38 × 10 ^-4） 。我们进一步描述了配偶之间表型相似的模式，其中配偶表现出六种神经和精神表型的相关性，包括抑郁症的疾病内相关性（R = 0.24-0.68，p < 0.001）以及焦虑和双相情感障碍之间的跨疾病相关性无序（R = 0.09–0.22，p < 10 ⁻⁹² ）。通过模拟种群，我们还发现选型交配会导致几代人的疾病易感性增加，并在携带罕见变异的家庭中出现“遗传预期”。我们在神经发育疾病队列中确定了几个家庭，其中先证者从每个受影响的父母那里继承了疾病相关基因的多个罕见变异。我们通过其与变异致病性的负相关关系进一步确定父母亲缘关系是神经发育障碍的危险因素，并提出父母亲缘关系通过增加儿童全基因组纯合性来调节疾病风险（R = 0.05-0.26，p < 0.05）。我们的结果强调了评估父母表型和基因型对于预测携带罕见可变表达变异的儿童特征的实用性，并暗示选型交配是这些家庭中疾病严重程度增加的危险因素。