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International Team Links Common Gene Variants to Human Brain Structure Volume

NEW YORK (GenomeWeb) – An international team of researchers has found a handful of gene variants that seem to influence human brain structures, findings that could have implications for neuropsychiatric conditions.

As part of the Enhancing Neuro Imaging Genetics through Meta-Analysis consortium, researchers led by Sarah Medland from the QIMR Berghofer Medical Research Institute in Australia conducted a genome-wide association study that drew on more than 30,700 people from 50 different cohorts to search for variants linked to differences in the volume of various brain structures, as determined by magnetic resonance imaging. 

As they reported in Nature today, the researchers uncovered five novel genetic variants that appear to influence the volumes of the putamen and the caudate nucleus, both of which are part of the basal ganglia. They also found three previously known loci that seem to affect hippocampal volume and intracranial volume. Some of these variants were in genes with roles in brain development, the researchers noted.

"Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction," Medland and her colleagues wrote in their paper.

She and her colleagues collected measurements of seven subcortical brain structures and overall intracranial volume using MRIs. To find common genetic variants linked to the size of these brain structures, the researchers performed a GWAS on a discovery set of 13,171 people of European ancestry.

Their meta-analysis of these discovery samples yielded six loci with genome-wide significance: one linked to intracranial volume, two with hippocampal volume and three with putamen volume. An additional two loci had suggestive associations with amygdala volume, one with putamen volume, and one with caudate nucleus volume, the researchers added.

Eight loci linked to subcortical brain structure volume were replicated in an independent cohort of nearly 17,550 people.

These loci, the researchers noted, were each associated with between 0.51 percent and 1.40 percent difference in volume and could explain a small — 0.17 percent to 0.52 percent — portion of the phenotypic variance seen. All together, these variants accounted for between 7 percent and 15 percent of the phenotypic variance.

The variants Medland and her colleagues identified influenced specific parts of the brain, rather than affecting multiples structures in the brain.

Four of the variants — located near KTN1, in DCC, in BCL2L1, and in DLG2 — affected putamen volume. KTN1 encodes the protein kinectin, which is involved in organelle transport, and DCC plays a role in axon guidance and migration especially in the striatum as it develops. Also, BCL2L1 encodes an anti-apoptotic factor, and DLG2 encodes the postsynaptic density 93 protein, which has a role in organizing channels in the postsynaptic density and is expressed in the striatum during development.

Variants in DLG2, the researchers noted, have been associated with learning and cognitive flexibility as well as with schizophrenia.

Other variants, like one near HRK and one in MSRB3, were linked with hippocampal volume, and a locus near FAT3, which encodes a cadherin that is expressed in the nervous system during embryonic development, is linked to caudate nucleus volume.

"Many seem to exert their effects through known developmental pathways including apoptosis, axon guidance, and vesicle transport," the researchers said.

The strongest association, the researchers said, was between the rs945270 locus —near KTN1 — and putamen volume. They noted that there is a lone epigenetic mark in this region, suggesting that it may play a role in gene regulation.

ChIP-seq analysis uncovered a new variant, rs8017172, that is in full linkage disequilibrium with rs945270. This variant, the researchers further reported, is within the binding site of the CTCF transcription regulation in embryonic stem cells.

The researchers also searched for whether this variant was associated with the expression of other genes within the region. They identified and replicated the effect of rs945270 on KTN1 expression in the frontal cortex and in the putamen.

KTN1 encodes kinectin, which the researchers said is found in the dendrites and soma of neurons, not the axons. Neurons with higher levels of kinectin have larger cells bodies, and, they added, knocking down kinectin affects cells' shape.

"The volumetric effects identified here may therefore reflect genetic control of neuronal cell size and/or dendritic complexity," the researchers said.

In a separate cohort of 1,541 healthy adolescents, the researchers found that the allelic effects of rs945270 were localized to regions along the superior and lateral putamen bilaterally. Additionally, they reported that each C allele was linked to an increase in volume along certain anterior superior regions.

"Discovery of common variants affecting the human brain is now feasible using collaborative analysis of MRI data, and may determine genetic mechanisms driving development and disease," the researchers said.