Genetic Factors for Neuropsychiatric Disorders Influence Brain Structure

Jacquelyn K. Beals, PhD

November 09, 2010

November 9, 2010 (Washington, DC) — Genetic variants associated with increased risk for neuropsychiatric disorders are associated with altered brain structure in apparently healthy individuals who carry these variants, according to a new study by Dutch researchers. Their finding raises the potential for using brain structure as an "intermediate phenotype" in identifying risk genes associated with neuropsychiatric disorders.

Barbara Franke, PhD, associate professor of molecular psychiatry, Department of Human Genetics and Department of Psychiatry, Institute for Genetic & Metabolic Diseases, Radboud University Nijmegen Medical Center, the Netherlands, presented the study findings here at American Society of Human Genetics 60th Annual Meeting.

Altered regional brain structure is often seen in patients who have neuropsychiatric disorders, although the relation between brain structure and pathology is poorly understood. "There are basically 2 scenarios: the alterations that we see mediate the increased risk for mental disorders; and the alterations are epiphenomena and, although they co-occur with disease susceptibility, they do not contribute to them," said Dr. Franke via email to Medscape Medical News after her presentation.

"The fact that we find brain structure alterations for so many psychiatric risk genes suggests that [the first option] is more likely, and [the alterations] are part of disease etiology," Dr. Franke observed.

The Brain Imaging Genetics (BIG) study enrolled more than 1500 healthy participants, with a mean age of 28 years. Structural brain images (1.5 or 3 Tesla magnetic resonance imaging [MRI] scans) of each participant were analyzed to determine the volume of certain brain regions. Genotypes were obtained for several specific candidate genes, and genome-wide genotyping was performed on 1000 participants.

CACNA1C was among the candidate genes tested because of its genome-wide association study (GWAS)-level association with bipolar disorder. The literature has also reported associations between CACNA1C variants and risk for unipolar depression, schizophrenia, and autism (in the Timothy syndrome).

The investigators found a group of single-nucleotide polymorphisms (SNPs) in CACNA1C that strongly affected brain stem volume (n = 600; P = 3.62 × 10–5). This result was obtained in 2 independent sets of participants, and volume comparisons were confirmed with Voxel-based morphometry — a technique of neuroimaging analysis used to study differences in brain anatomy and compare image volumes across brains.

The brain stem exerts central control over cognitive, motor, affective, and arousal functions, and "constitutes an interesting novel mode of action of risk factors for bipolar disease," the researchers note in the abstract.

"Brain stem might play a role [in bipolar disease], as it is very central to cognition," Dr. Franke told Medscape Medical News. "It contains the nuclei that synthesize the monoaminergic neurotransmitters that have been implicated in psychiatric disorders. . . . For the brain stem finding, we actually see volume differences in the white matter, which is likely to indicate alterations in myelination or in the number of nerves running through this part of the brain," she said.

Another analysis noted a significant decrease in the volume of the entorhinal cortex in individuals with the Alzheimer's disease–associated risk SNP of CR1. Too little of the protein normally produced by CR1 can lead to chronic inflammation in the brain, and is thought to contribute to Alzheimer's development. This volume decrease affects the grey matter, Dr. Franke reported. The association was found in an initial sample of 430 participants, and was replicated in 492 additional individuals (using small-volume correction of 0.032 and 0.039, respectively).

This was also seen with SORL1, a neuronal apolipoprotein E receptor, the variants of which seem to increase the production of amyloid beta. "It is grey matter that is affected," said Dr. Franke, "which would mean either less or smaller neurons."

An initial GWAS of amygdala volume (in 600 participants) demonstrated association with CDH13, among other genes thought to be associated with psychiatric disease risk. CDH13 variants have been associated with attention deficit hyperactivity disorder, schizophrenia, addiction, and even traits such as neuroticism and extraversion.

"The preliminary data I presented on the GWAS of amygdala volume are directed at identifying genes regulating amygdala volume, with the idea that these genes (given the link between brain structure and function) would be good candidate genes for an altered amygdala function, as we find it in several psychiatric disorders like depression and anxiety disorders," said Dr. Franke.

"I think the [MRI] work is beginning to have a lot of potential for the [study of] brain aging," said session comoderator Gyungah Jun, PhD, research assistant professor, Departments of Medicine (Genetics Program), Ophthalmology, and Biostatistics at Boston University School of Medicine, Massachusetts, in talking with Medscape Medical News. "Not the specific disease, such as Alzheimer's or any other specific bipolar disorder; [it is] not just the neuropsychiatric disorders. This may be just a potential tool for studying brain aging or . . . common causes of neurodegenerative disease."

Summarizing her approach, Dr. Franke added: "The general idea is that of the intermediate phenotypes being traits that are 'closer' to the genes than the clinical phenotypes, and also less genetically complex. Therefore, we hypothesize that our studies will have increased power to identify genes for psychiatric disorders, compared with studies relying on clinical phenotypes."

Dr. Franke and Dr. Jun have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 60th Annual Meeting: Abstract 77. Presented November 3, 2010.

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