Novel genetic loci underlying human intracranial volume identified through genome-wide association

Abstract

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth.

Breaking down the genetics of depression using brain endophenotypes

“…In comparison, the 8 ICV SNPs explained 0.099 to 0.27% of the variance [78], the 6 hippocampus SNPs 0.092 to 0.32% [77], the 4 putamen SNPs 0.14 to 0.32, while the 1 SNP associated with caudate explained 0.11% of the trait variance [76]. These results are summarised in Figure Our results align with the hypothesis of a simpler genetic architecture of brain structural phenotypes compared to psychiatric diagnoses.…”

“…Another CHARGE paper focused on white matter lesion [565]. In addition to reporting new associated variants, these larger studies also confirmed the previously identified associations [76,78]. In addition, a new manuscript is in preparation that focuses on cortical thickness and surface area.…”

“…Since the sections above were published, the ENIGMA and CHARGE consortium [386] reported new variants associated with ICV [78] and hippocampal volume using >30,000 brain scans [76]. Another CHARGE paper focused on white matter lesion [565].…”

“…The sample size reached over the years makes ENIGMA one of the most powerful meta-analytic sample to study the genetics of the brain (the other being the CHARGE consortium). For example, the ENIGMA sample grew from ~8k scans in the first GWAS [506] on ICV and hippocampal volume, to ~30k in the most recent analyses (with CHARGE) [76,78] and we can expect the sample size to increase again for the cortical analysis. However, the number of phenotypes considered has increased even faster (from 2 to 8 subcortical volumes to 68 cortical measurements) and we can expect even more phenotypes to be included in future projects (e.g.…”

“…Finally we came back to the hypothesised simpler genetic architecture of endophenotypes compared to psychiatric diagnoses [16]. We contrasted published SNP effect sizes on brain phenotype (ICV, hippocampal volume, putamen, nucleus accumbens) [76][77][78] with those of psychiatric traits (depression, schizophrenia) [15,79] and evaluated if they align with the theory. BATS [35,80]), which began in 1992 when twins were recruited from primary and secondary schools in the greater Brisbane area via media appeals and by word of mouth.…”