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International Team Publishes Large Neuroticism GWAS

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Neuroticism is not a consequence of key common SNPs with strong effects, but may result from more subtle and widespread genetic changes combined with environmental influences, according to a recent study.

In a paper appearing online this month in PLoS ONE, an international research team, including investigators from GlaxoSmithKline, described the results of a genome-wide association study involving more than 2,200 people. Though they found potential risk SNPs in several genes — including one variant that's apparently related to age-related increases in neurotic traits — the researchers did not find strong genetic links between neuroticism and any of these new or previously described variants.

"These results suggest common SNP variation does not strongly influence neuroticism," lead author Federico Calboli, a statistical and population genetics researcher at Imperial College London, and his co-authors wrote. "[O]ur results effectively exclude the existence of loci having a major effect on neuroticism."

Individuals with neurotic personality types, characterized by a set of traits including nervousness and excessive reactions to stress, are thought to be at increased risk of depression, anxiety disorders, and dementia.

Neuroticism seems to be somewhat heritable, the researchers explained, with previous studies having detected neuroticism-related linkage peaks on several chromosomes. But while associated SNPs have been detected in a handful of genes, they added, finding significant, verifiable loci underlying neuroticism has been tricky.

To further explore the genetics of neuroticism, Calboli and his colleagues genotyped 2,235 Caucasian individuals from a Swiss neuroticism study using the Affymetrix GeneChip Human Mapping 500K array. Study participants, who ranged in age from 36 to 70 years old, were interviewed and completed a personality questionnaire aimed at gauging neuroticism.

After their quality control steps, the team was left with information for 430,000 autosomal SNPs. To this, they added imputation data on another 1.2 million variants gleaned from CEU HapMap samples.

Although they found that neuroticism showed less heritability in their sample group than reported in past studies, the researchers did find some SNPs that appear to be weakly associated with such personality traits.

Among them: an imputed SNP in PDE4D, a phosphodiesterase 4D gene fingered as a potential neuroticism contributor in past research, imputed variants in the sodium/potassium transporting ATPase interacting 2 gene NKAIN2, and genotyped and imputed SNPs in the arrestin domain containing 4 gene ARRDC4.

The researchers also tracked down several variants in the proteoglycan gene GPC6 that appear to correlate with increases in neurotic traits in older individuals — a finding that they say could shift the view of neuroticism if holds in future validation studies.

And, they say, the age-related variant is also intriguing given GPC6's apparent contribution to the Wnt pathway, a signaling pathway involved in neural development and nervous system function.

Still, the team emphasized that none of the variants detected in the current study showed strong ties to neuroticism, arguing against common neuroticism-associated loci with major effects in the Swiss group tested. Instead, they explained, numerous spots in the genome and/or yet undefined environmental factors might incrementally increase risk for neurotic personality traits.

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