両親の特徴から子供の神経発達疾患を予測する(Predicting neurodevelopmental disease in children from parent’s traits)

2024-02-08

2024-02-07 ペンシルベニア州立大学(PennState)

新しい研究によると、自閉症や統合失調症などの神経発達障害や精神障害の予後を予測するのは困難であり、多くの異なる遺伝子や環境要因に影響される可能性があります。しかし、ペンシルバニア州立大学の研究者らは、これらの障害の予測には、遺伝子変異だけでなく、親がこれらの障害の特徴を示すかどうかを評価することがより正確な方法を提供することを示しています。研究では97,000の家族を対象にして、親と子供の両方の症状を評価し、遺伝的特徴と親の特性が子供の病気の経過にどのように影響するかを評価しました。

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親の遺伝的近縁性と同系交配が表現型変異の病原性に寄与する Assortative mating and parental genetic relatedness contribute to the pathogenicity of variably expressive variants

Corrine Smolen,Matthew Jensen,Lisa Dyer,… Bertrand Isidor,Jane Juusola,Santhosh Girirajan
American Journal of Human Genetics Published:November 17, 2023
DOI:https://doi.org/10.1016/j.ajhg.2023.10.015

Summary

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.