Rare variants in TMEM132D in a case-control sample for panic disorder

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Genome-wide association studies (GWAS) identify common variants linked to diseases, but these explain limited heritability.
• Rare genetic variants may play a more significant role in common diseases than previously assumed.
• The TMEM132D locus has been previously associated with panic disorder and anxiety severity.

Purpose of the Study:

• To investigate the contribution of rare genetic variants to the risk of anxiety disorders.
• To re-sequence the TMEM132D locus, including all exons, to identify novel variants.
• To analyze genetic variants in patients with anxiety disorders and healthy controls.

Main Methods:

• Next-generation sequencing (NGS) was used to re-sequence 40kb of the TMEM132D locus in 300 anxiety disorder patients and 300 healthy controls.
• A pooled sequencing approach was employed, with results verified by individual re-genotyping.
• Identified variants were analyzed for frequency and potential functional impact, including comparison with public datasets.

Main Results:

• 371 genetic variants were identified in the TMEM132D locus, with 247 being novel.
• 15 novel non-synonymous variants were found, with 76% having a minor allele frequency below 5%.
• An overrepresentation of functional coding variants was observed in healthy controls compared to cases, and cases showed a higher rate of private coding variants.

Conclusions:

• While common variants in TMEM132D did not show additional association with panic disorder, rare and putatively functional variants may contribute to anxiety disorder risk.
• The findings suggest that both common and rare variants within TMEM132D are implicated in the susceptibility to anxiety disorders.
• Further research into the role of rare TMEM132D variants in anxiety pathogenesis is warranted.