As an essential part of the central nervous system, white matter coordinates communications between different brain regions and is related to a wide range of neurodegenerative and neuropsychiatric disorders. Previous genome-wide association studies (GWASs) have uncovered loci associated with white matter microstructure. However, GWASs suffer from limited reproducibility and difficulties in detecting multi-single-nucleotide polymorphism (multi-SNP) and epistatic effects. In this study, we adopt the concept of supervariants, a combination of alleles in multiple loci, to account for potential multi-SNP effects. We perform supervariant identification and validation to identify loci associated with 22 white matter fractional anisotropy phenotypes derived from diffusion tensor imaging. To increase reproducibility, we use United Kingdom (UK) Biobank White British (n = 30,842) data for discovery and internal validation, and UK Biobank White but non-British (n = 1927) data, Europeans from the Adolescent Brain Cognitive Development study (n = 4399) data, and Europeans from the Human Connectome Project (n = 319) data for external validation. We identify 23 novel loci on the discovery set that have not been reported in the previous GWASs on white matter microstructure. Among them, three supervariants on genomic regions 5q35.1, 8p21.2, and 19q13.32 have P-values lower than 0.05 in the meta-analysis of the three independent validation data sets. These supervariants contain genetic variants located in genes that have been related to brain structures, cognitive functions, and neuropsychiatric diseases. Our findings provide a better understanding of the genetic architecture underlying white matter microstructure.

中文翻译：

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超变体的识别和验证揭示了与人类白质微结构相关的新位点

作为中枢神经系统的重要组成部分，白质协调不同大脑区域之间的通信，并与多种神经退行性和神经精神疾病相关。之前的全基因组关联研究（GWAS）已经发现了与白质微观结构相关的位点。然而，GWAS 的重现性有限，且难以检测多单核苷酸多态性 (multi-SNP) 和上位效应。在本研究中，我们采用超变体的概念，即多个位点中等位基因的组合，来解释潜在的多 SNP 效应。我们进行超变识别和验证，以识别与源自扩散张量成像的 22 个白质分数各向异性表型相关的位点。为了提高可重复性，我们使用英国 (UK) 生物银行白人英国 (n = 30,842) 数据进行发现和内部验证，以及英国生物银行白人但非英国 (n = 1927) 数据，欧洲人来自青少年大脑认知发展研究 ( n = 4399）数据，以及来自人类连接组项目的欧洲人（n = 319）数据进行外部验证。我们在发现集上确定了 23 个新位点，这些位点在之前的白质微观结构 GWAS 中尚未报道。其中，基因组区域5q35.1、8p21.2和19q13.32上的三个超变体在三个独立验证数据集的荟萃分析中P值低于0.05。这些超变体包含位于与大脑结构、认知功能和神经精神疾病相关的基因中的遗传变异。我们的研究结果提供了对白质微观结构背后的遗传结构的更好理解。