Genome-wide association studies of brain imaging phenotypes in UK Biobank

Abstract

The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and structural brain imaging phenotypes from UK Biobank (discovery dataset 8,428 subjects). Here we show that many of these phenotypes are heritable. We identify 148 clusters of associations between single nucleotide polymorphisms and imaging phenotypes that replicate at P < 0.05, when we would expect 21 to replicate by chance. Notable significant, interpretable associations include: iron transport and storage genes, related to magnetic susceptibility of subcortical brain tissue; extracellular matrix and epidermal growth factor genes, associated with white matter micro-structure and lesions; genes that regulate mid-line axon development, associated with organization of the pontine crossing tract; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide insights into the genetic architecture of the brain that are relevant to neurological and psychiatric disorders, brain development and ageing.

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

“…Though our sample size is smaller than prior studies (8,29), a preliminary analysis using FreeSurfer software (http://surfer.nmr.mgh.harvard.edu/) showed no detectable difference in volume between genotypes in any brain region, suggesting that MRI signal changes in A391T carriers likely result from differences in the concentrations of paramagnetic ions such as Mn (data not shown). ANOVA analyses each element showed that only Mn was statistically different between genotypes (F = 6.472, p = 0.0022, DF = 2).…”

“…Previous studies have linked the rs13107325 minor allele (T) with brain MRI changes attributed to regional volumetric differences (8,29). Given the paramagnetic properties of Mn and its known effect on MRI relaxation time (30)(31)(32), we hypothesized that the signal change resulted from changes in local concentrations of Mn and related ions.…”

“…Interestingly, A391T is protective against Parkinson disorder, presumably from reduced uptake of Mn in to the pallidum or SN (10). Two recent studies associated A391T with brain MRI signal changes attributed to volumetric differences including increased gray matter in the caudate, putamen and cerebellum (8,29). MRI signal is affected by any factor influencing the magnetic field including Fe and Mn concentrations (45).…”

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

“…While rare variants can have large effects, they do not explain the majority of variability in brain structure within a population. To address this, consortia have recently identified hundreds of genome‐wide significant common variant loci, each generally composed of multiple correlated SNPs, that impact human brain structure, including intracranial volume (seven loci), subcortical volumes (38 loci), ventricular volumes (seven loci), cortical surface area and thickness (150 loci), and even white matter anatomy (225 loci) . No variants have yet been identified impacting brain function as measured through fMRI, though a handful of variants reach genome‐wide significance for oscillatory brain activity as measured with electroencephalograms (two loci) …”

“…To address this, consortia have recently identified hundreds of genome-wide significant common variant loci, each generally composed of multiple correlated SNPs, that impact human brain structure, including intracranial volume (seven loci), 7,8,[81][82][83] subcortical volumes (38 loci), 6,8,70,81,84,85 ventricular volumes (seven loci), 86 cortical surface area and thickness (150 loci), 74,87 and even white matter anatomy (225 loci). 71 No variants have yet been identified impacting brain function as measured through fMRI, 71 though a handful of variants reach genome-wide significance for oscillatory brain activity as measured with electroencephalograms (two loci). 88 Before these large consortia identified replicable genetic associations, it was hypothesized that structural and functional neuroimaging traits were 'closer to the underlying biology.'…”