Genome-wide autozygosity is associated with lower general cognitive ability.
Genome-wide autozygosity is associated with lower general cognitive ability.
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DOI：
10.1038/mp.2015.120
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发表时间：
2016-06
影响因子：
11
通讯作者：
Keller MC
中科院分区：
文献类型：
--
作者：
Howrigan DP;Simonson MA;Davies G;Harris SE;Tenesa A;Starr JM;Liewald DC;Deary IJ;McRae A;Wright MJ;Montgomery GW;Hansell N;Martin NG;Payton A;Horan M;Ollier WE;Abdellaoui A;Boomsma DI;DeRosse P;Knowles EE;Glahn DC;Djurovic S;Melle I;Andreassen OA;Christoforou A;Steen VM;Hellard SL;Sundet K;Reinvang I;Espeseth T;Lundervold AJ;Giegling I;Konte B;Hartmann AM;Rujescu D;Roussos P;Giakoumaki S;Burdick KE;Bitsios P;Donohoe G;Corley RP;Visscher PM;Pendleton N;Malhotra AK;Neale BM;Lencz T;Keller MC
近亲繁殖衰退是指遗传亲属的后代适应性较低。这种降低的适应性是由基因组中两个相同的染色体片段（同源性）遗传引起的，这可能暴露出（部分）隐性有害突变的影响。即使在远交种群中，由于双亲之间的隐性亲缘关系，同源性也会在不同程度上发生。使用密集的全基因组SNP数据，我们在一个包含4，854名欧洲血统参与者的随机样本中研究了自体接合性与认知能力相关的程度。我们使用纯合性-连续多个纯合SNP-来估计整个基因组的纯合片段。我们发现，增加水平的同源性预测较低的一般认知能力，并估计下降0.6标准差之间的后代的第一堂兄弟（p = 0.003 - 0.02，取决于模型）。这种影响主要来自长而罕见的自体接合的神经束，理论预测其比短而常见的神经束更可能有害。在校正多个全基因组测试后，自体接合片段的关联作图没有揭示任何超出预测机会的特定区域。观察到的效应量与已知血缘关系的后代认知能力下降的研究一致。这些发现表明，多个隐性或部分隐性等位基因在一般认知能力中的作用，并且在进化时间内，降低一般认知能力的等位基因已被选择。
Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide SNP data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4,854 participants of European ancestry. We used runs of homozygosity—multiple homozygous SNPs in a row— to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 standard deviations among the offspring of first cousins (p = 0.003 - 0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome-wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.