NEW YORK – A team led by investigators in China has tracked down dozens of new and known genes associated with neuroticism with an association study approach focused on rare and common variants in protein-coding parts of the genome, while highlighting genetic features shared with neuropsychiatric conditions.
"These neuroticism-associated genes present plentiful relationships with various neuropsychiatric phenotypes, and some of them are druggable, suggesting the potential as therapeutic interventions for neuropsychiatric disorders," co-first and co-corresponding authors Jin-Tai Yu and Wei Cheng, neurology and neurological disorder researchers with Fudan University's Huashan Hospital, and their colleagues wrote in Nature Human Behaviour on Thursday.
Using exome sequence data for 454,787 European ancestry individuals from the UK Biobank, the researchers began by searching for variants associated with 13 traits linked to neuroticism, a personality trait marked by negative emotional responses such as worry, anxiety, guilt, and irritability in response to life's challenges. From there, they estimated the contributions that rare and common variants make to neuroticism heritability, and turned to allele frequency and functional annotation clues for collapsing analyses focused on flagging neuroticism genes.
"This study represents the largest exome-wide association study (ExWAS) of neuroticism to date, offering informative insights into the contributions of rare and common coding variants to neuroticism," co-first author Xin-Rui Wu, with Fudan University's department of neurology and National Center for Neurological Disorders at Huashan Hospital, said in an email, adding that the team's findings "provide novel perspectives on the genetic architecture and potential biological mechanism underlying neuroticism."
All told, the team's analyses led to 56 neuroticism-associated genes, including genes previously linked to brain structure features, cognitive capabilities, and other neuropsychiatric conditions such as depression. The collection included 18 genes not implicated in neuroticism in the past.
On the rare variant side, for example, the researchers highlighted 12 new neuroticism-related genes and two genes linked to neuroticism through prior genome-wide association studies. From 78 common variants associations, meanwhile, they flagged six genes not implicated in neuroticism in past studies.
The team went on to validate the gene-level findings with a meta-analysis that included tens of thousands of UK Biobank participants from four ancestry groups, including non-British white, Asian, African, or mixed ancestry individuals. The associations were further validated with the help of summary data from a genome-wide association study of neuroticism that involved more than 59,200 research-consented 23andMe customers.
"Future experimental research is needed to investigate the specific pathways through which the genetic variants influence neuroticism," Wu noted. "More importantly, given the plentiful phenotypic and genetic correlations between neuroticism and many neuropsychiatric disorders, our findings hold promise for clinical advancements, fostering the development of precise treatments and interventions for neuropsychiatric disorders."
Along with subsequent Mendelian randomization analyses on causal associations involving expression of the neuroticism-related genes, the investigators explored the genetic overlap between neuroticism and neuropsychiatric phenotypes such as depression.
Going forward, the team plans to expand its analyses to include large-scale whole-genome sequencing data, Wu said. "We believe that, from earlier GWAS to the current ExWAS and the upcoming WGS efforts, the genetic architecture of neuroticism will gradually be fully understood. This will help to illuminate the biological pathways underpinning neuroticism and related neuropsychiatric disorders."