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Dozens of Genetic Variants Influence Volume of Subcortical Brain Structures

NEW YORK – A team led by researchers in the Netherlands has uncovered four dozen genetic loci that influence the size of various brain structures.

The researchers, led by Erasmus University Medical Center's Arfan Ikram, conducted a genome-wide association study of the volume of seven subcortical brain structures. These structures —including the nucleus accumbens, amygdala, and brainstem — are involved in key brain functions and have been implicated in cognitive, psychiatric, and movement disorders.

For their analysis, Ikram and his colleagues combined data from nearly 40,000 individuals. As they reported in Nature Genetics today, they found 48 loci associated with variability in the volume of these brain structures and uncovered nearly 200 candidate genes that may influence volume, including genes previously linked to neurodevelopment, apoptosis, and inflammation.

"Our findings expand the current understanding of the genetic variation related to subcortical structures, which can help in the identification of novel biological pathways of relevance to human brain development and disease," the researchers wrote in their paper.

For their analysis, Ikram and his colleagues used genotyping and MRI data collected by the Cohorts of Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium, and the UK Biobank. Through their analysis of 37,741 individuals of European ancestry in these datasets, the researchers teased out 48 independent SNPs with genome-wide significance across the seven subcortical brain structures.

The researchers further examined these 48 SNPs in a cohort of 769 African Americans and 341 Asians to gauge their association with brain structure volume across ethnicities. They found that the direction of association was the same for 13 SNPs across all ethnicities, though they noted that their sample was small.

The 48 SNPs the researchers identified in the European cohorts connected some 199 genes to brain structure volume based on an analysis using the LocusZoom tool on postmortem brains from the Religious Order Study and the Rush Memory and Aging Project.

Nearly 60 percent of these candidate genes are strongly conserved in the Drosophila genome, the researchers noted, suggesting the genomic architecture of the central nervous system has been conserved throughout evolution.

Additionally, many of the candidate genes the researchers uncovered may influence the volume of more than one subcortical brain structure. For instance, SNPs near the gene KTN1 were associated not only with nucleus accumbens size but also with the volume of the caudate nucleus and the globus pallidus, indicating that these regions might be involved in determining the volume of various brain regions during development.

Other genes the researchers reported, such as PTPN1, ALPL, and SLC20A2, are also involved in neurodevelopment. PTPN1 is thought to be a key regulator of neural differentiation and is being explored as a therapy in mouse models of Rett syndrome, while ALPL mediates neuronal differentiation during early development and SLC20A2 encodes an inorganic phosphate transporter.

Other SNPs, meanwhile, implicate genes involved in autophagy and apoptosis, including DRAM1 and FOXO3, which are both linked to brain stem volume. DRAM1 encodes a lysosomal membrane protein that has a role in TP53-mediated autophagy and apoptosis, and FOXO3 has recently been tied to a conserved astrocyte network that is linked to stress and sleep, as well as to Huntington's disease and longevity. A number of other SNPs have similarly highlighted the potential role of candidate genes such as ANKRD42, IL27, and TRIM4 that are involved in inflammation, immunity, and infection.

"The majority of the variants identified in this analysis point to genes involved in neurodevelopment, regulation of neuronal apoptotic processes, synaptic signaling, axonal transport, inflammation/immunity, and susceptibility to neurological disorders," the researchers wrote.