7. INVESTIGATING POLYGENIC RISK AND RARE CNVS IN PARENT-OFFSPRING TRIOS WITH TRICHOTILLOMANIA AND EXCORIATION DISORDER

Trichotillomania and excoriation disorder are obsessive-compulsive related disorders characterized by hair-pulling or skin-picking, respectively, leading to significant distress and impairment. These body-focused repetitive behavior disorders (BFRBs) are difficult to treat, with few first-line interventions, highlighting the need for more etiologic research to inform treatments. While previous research suggests the role of shared genetic factors between trichotillomania and excoriation disorder, the use of genome-wide approaches in studying BFRBs has been limited. This study aims to advance our understanding of the genetic architecture of BFRBs by examining the role of polygenic risk for neuropsychiatric conditions and rare copy-number variants (CNVs) in parent-offspring trios with BFRBs. Individuals with trichotillomania and/or excoriation disorder, as well as their biological parents, were recruited and enrolled in an ongoing genetic study at Yale. Parent-offspring trios from 110 families were genotyped using the Illumina Infinium Global Screening Array-24 v3.0 BeadChip. After quality control, 100 parent-offspring trios (288 individuals) were analyzed. The probands were predominantly female (94%) and of European ancestry (95%). Imputation was performed, and polygenic risk scores (PRS) were calculated using PRS-CS with the summary statistics from genome-wide association studies of related psychiatric conditions, including obsessive-compulsive disorder (OCD), Tourette’s disorder, depression, anxiety, ADHD, autism, and cross-disorder. The polygenic transmission disequilibrium test (pTDT) and a two-sided, one-sample t-test were used to test for overtransmission of PRS from parents to probands. In these same trios, we examined the frequency of rare de novo and inherited CNVs (allele frequency < 1% in gnomAD) using PennCNV and cnvPartition. We focused on rare CNVs overlapping constrained genes (pLI > 0.9) and those previously associated with neurodevelopmental disorders or overlapping neurodevelopmental risk genes. Probands with BFRBs show an elevated burden of transmission of OCD polygenic risk from their parents (mean pTDT = 0.3, p = 0.01). PRS pTDT for other neuropsychiatric conditions were not significant in this sample. We identified 65 rare CNVs in probands with a rate of 0.34 rare deletions and 0.42 rare duplications per proband, of which 8 rare CNVs overlapped constrained genes. Exploratory pathway analyses of constrained genes show enrichment of pathways involved in synaptic organization and structure. We also identified 7 CNVs previously associated with neurodevelopmental disorders or overlapping neurodevelopmental risk genes. These findings provide new insights into the role of common and rare genetic variants in BFRBs. Our observation of an increased transmission of OCD polygenic risk in probands with trichotillomania or excoriation disorder is consistent with shared genetic liability across obsessive-compulsive related disorders. Though our sample size is small, the observed rate of rare CNVs is similar to those previously reported in associated conditions. Several rare CNVs also overlapped constrained genes intolerant to loss-of-function variation and neurodevelopmental risk genes, suggesting potential shared mechanisms. These findings contribute to our understanding of the genetic architecture of BFRBs, highlighting the discovery potential of larger genomic studies of BFRB parent-offspring trios.