Identification and validation of supervariants reveal novel loci associated with human white matter microstructure

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 (GWAS) have uncovered loci associated with white matter microstructure. However, GWAS suffer from limited reproducibility and difficulties in detecting multi-single nucleotide polymorphism (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 UK Biobank White British (n = 30,842) data for discovery and internal validation, and UK Biobank White but non-British (n = 1,927) data, European of Adolescent Brain Cognitive Development study (n = 4,399) data, and European of Human Connectome Project (n = 319) data for external validation. We identified 23 novel loci on the discovery set that have not been reported in the previous GWAS 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 datasets. 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.