Expression quantitative trait loci (eQTL) are genetic variants associated with gene expression. Using genome-wide genotype data, it is now possible to impute gene expression using eQTL mapping efforts. This approach can be used to analyse previously unexplored relationships between gene expression and heritable in vivo measures of human brain structural connectivity. Using large-scale eQTL mapping studies, we computed 6457 gene expression scores (eQTL scores) using genome-wide genotype data in UK Biobank, where each score represents a genetic proxy measure of gene expression. These scores were then tested for associations with two diffusion tensor imaging measures, fractional anisotropy (NFA = 14,518) and mean diffusivity (NMD = 14,485), representing white matter structural integrity. We found FDR-corrected significant associations between 8 eQTL scores and structural connectivity phenotypes, including global and regional measures (βabsolute FA = 0.0339-0.0453; MD = 0.0308-0.0381) and individual tracts (βabsolute FA = 0.0320-0.0561; MD = 0.0295-0.0480). The loci within these eQTL scores have been reported to regulate expression of genes involved in various brain-related processes and disorders, such as neurite outgrowth and Parkinson's disease (DCAKD, SLC35A4, SEC14L4, SRA1, NMT1, CPNE1, PLEKHM1, UBE3C). Our findings indicate that eQTL scores are associated with measures of in vivo brain connectivity and provide novel information not previously found by conventional genome-wide association studies. Although the role of expression of these genes regarding white matter microstructural integrity is not yet clear, these results suggest it may be possible, in future, to map potential trait- and disease-associated eQTL to in vivo brain connectivity and better understand the mechanisms of psychiatric disorders and brain traits, and their associated imaging findings.

译文

表达数量性状基因座 (eQTL) 是与基因表达相关的遗传变异。使用全基因组基因型数据,现在可以使用eQTL作图来估算基因表达。这种方法可用于分析基因表达与人类大脑结构连接的可遗传体内测量之间以前未探索的关系。使用大规模eQTL作图研究,我们使用英国生物库中的全基因组基因型数据计算了6457基因表达分数 (eQTL分数),其中每个分数代表基因表达的遗传代理度量。然后测试这些分数与两个扩散张量成像测量的相关性,即分数各向异性 (nfa   =   14,518) 和平均扩散率 (nmd   =   14,485),代表白质结构完整性。我们发现FDR校正了8个eQTL评分与结构连接表型之间的显着关联,包括全局和区域度量 (β 绝对fa   =   0.0339-0.0453; MD  =   0.0308-0.0381) 和单个区域 (β 绝对fa   =   0.0320-0.0561; MD  =   0.0295-0.0480)。据报道,这些eQTL评分中的基因座可以调节与各种脑相关过程和疾病有关的基因的表达,例如神经突生长和帕金森氏病 (DCAKD,SLC35A4,SEC14L4,SRA1,NMT1,CPNE1,PLEKHM1,UBE3C)。我们的研究结果表明,eQTL评分与体内大脑连通性的测量相关,并提供了传统的全基因组关联研究以前未发现的新信息。尽管这些基因的表达对白质微结构完整性的作用尚不清楚,但这些结果表明,将来有可能将潜在的性状和疾病相关的eQTL与体内大脑连接作图,并更好地了解其机制精神疾病和大脑特征,以及他们相关的影像学发现。

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