Thirty novel sequence variants impacting human intracranial volume.
Nawaz MS et al. 2022
Researchers performed a genome-wide association study meta-analysis of intracranial volume (ICV) using three GWAS summary statistics; ICV + HC from Iceland, ICV from the UKBiobank, and published GWAS summary data of ICV + head circumference (HC) from enhancing neuroimaging genetics through meta-analysis (ENIGMA) consortium and Early Growth Genetics (EGG) consortium. The meta-analysis included 42.9 million imputed variants available in the Icelandic and UK samples and 9.7 million in the ENIGMA/EGG sample. Previous GWAS studies on ICV or HC have reported 36 variants. Of those 36 variants, they replicated the association of 34 variants. Altogether, 64 ICV associations at 51 loci, including 30 novel, were significant and explain 5.0% of the variability in ICV. Specifically, these include rs11111293 in the LINC02456, rs12146713 in the NUAK1 gene, rs2066827 in the CDKN1B, rs10876450, rs78378222 in the TP53 gene, rs7254272 (novel), rs288326 in the FRZB, rs448162 (novel), rs9400239 in the FOXO3, rs11759026 in the CENPW gene. The rs9400239, rs11759026 and rs288326 are known to be related with body mass index, neuroticism and blood protein respectively.
Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume (n = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder.