Genome-Wide Association Analysis of Neonatal White Matter Microstructure

Abstract

A better understanding of genetic influences on early white matter development could significantly advance our understanding of neurological and psychiatric conditions characterized by altered integrity of axonal pathways. We conducted a genome-wide association study (GWAS) of diffusion tensor imaging (DTI) phenotypes in 471 neonates. We used a hierarchical functional principal regression model (HFPRM) to perform joint analysis of 44 fiber bundles. HFPRM revealed a latent measure of white matter microstructure that explained approximately 50% of variation in our tractography-based measures and accounted for a large proportion of heritable variation in each individual bundle. An intronic SNP in PSMF1 on chromosome 20 exceeded the conventional GWAS threshold of 5 x 10−8 (p = 4.61 x 10−8). Additional loci nearing genome-wide significance were located near genes with known roles in axon growth and guidance, fasciculation, and myelination.

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

“…For the detected protein-coding genes, we perform lookups in the NHGRI-EBI GWAS catalog ( Buniello et al 2019 ) and previous GWASs for white matter to explore their previously reported gene-trait associations. Our results replicate 415 genes reported by Zhao et al (2021a) and some other genes reported in previous studies for human white matter ( Sprooten et al 2013 , 2014 ; Verhaaren et al 2015 ; Jian et al 2018 ; Rutten-Jacobs et al 2018 ; Zhao et al 2021b ; Zhang et al 2021 ) and find 204 novel genes ( Supplemental Table S7 ). Of the 619 detected genes, 227 have previously been implicated in cognitive function, education, neuroticism, neuropsychiatric disorders, neurodegenerative diseases, and reaction time, such as ARIH2 ( Lee et al 2018 ; Kulminski et al 2022 ) and PTCH1 ( Nagel et al 2018 ; Thorp et al 2021 ; Okbay et al 2022 ).…”

Genetic evidence for serum amyloid P component as a drug target for treatment of neurodegenerative disorders

“…GWAS Catalog look-ups for the effects of genetic variants in APCS identified a previously reported association with white-matter microstructure 34 (Fig. S3; Table S9).…”

Genetic Influences on the Developing Young Brain and Risk for Neuropsychiatric Disorders

“…In adults, estimates for FA range from 72% to 88% ( 25 ). Despite large variations in heritability estimates across individual tracts, a single latent measure of white matter microstructure accounts for a great deal of heritable variation in neonates (50%) ( 26 ). Similarly, individual differences in regional CT and SA appear to be driven by a common set of genetic factors influencing cortical structure at the global level ( 19 ).…”

“…The investigators also compared their results to large-scale neuroimaging GWASs in adolescents and adults and concluded that genetic determinants of global brain volumes are highly distinct at different ages. In a subsequent GWAS of white matter microstructure in neonates, an intronic SNP in PSMF1 was significantly associated with a tractography-based factor capturing shared variation in FA across 44 white matter bundles ( 26 ). Additional loci nearing genome-wide significance were in or near genes with roles in axon growth and guidance, fasciculation, and myelination including B3GAT1 , TENM2 , NFATC1 , and MAP3K13 .…”

“… Zhang et al. , 2021 ( 26 ) 471 Neonates (days post conception 293.4 ± 16.6) Multiancestry An intronic SNP in the gene PSMF1 was significant for a tractography-based factor that captured shared variation in fractional anisotropy across 44 white matter bundles. PPAR, peroxisome proliferator-activated receptor; SNP, single nucleotide polymorphism.…”