Paternal-age-related de novo mutations and risk for five disorders
Paternal-age-related de novo mutations and risk for five disorders
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DOI：
10.1038/s41467-019-11039-6
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发表时间：
2019-07-10
影响因子：
16.6
通讯作者：
Robinson, Elise B.
中科院分区：
文献类型：
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作者：
Taylor, Jacob L.;Debost, Jean-Christophe P. G.;Robinson, Elise B.
父亲高龄与后代患精神和发育障碍的风险之间存在着既定的关联。这些通常归因于基因突变，特别是随着父亲年龄的增加而积累的从头单核苷酸变异（dnSNV）。然而，男性生殖系中此类突变的实际风险程度尚不清楚。量化这种风险将澄清延迟亲子鉴定的临床意义。使用父母-子女三重全外显子组测序数据，我们估计了父亲年龄相关dnSNVs与五种疾病风险之间的关系：自闭症谱系障碍（ASD），先天性心脏病，神经发育障碍伴癫痫，智力残疾和精神分裂症（SCZ）。使用丹麦登记数据，我们调查是否流行病学协会之间的每种疾病和老年父亲是一致的dnSNVs的估计作用。我们发现，父亲年龄相关的dnSNVs赋予这些疾病的风险很小。对于ASD和SCZ，与延迟生育的流行病学关联反映了可能不会随着年龄而增加的因素。
There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.