Genomics and Phenomics of Obsessive-Compulsive and Related Disorders

• Main Author: Ivankovic, Franjo
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2022
• Subjects: Bioinformatics; Epidemiology; Genetics
• ISBN: 9798380604666

Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) are neuropsychiatric disorders with onset in childhood affecting 0.6% and 2.3% of people, respectively. TS and OCD are also highly comorbid with 50-60% of TS patients endorsing OCD, and 10% of OCD patients endorsing TS. Both TS and OCD are highly heritable, with heritability estimates ranging 30% to 60% in family and twin studies. Despite substantial heritability estimates, little is known about underlying genetic mechanisms of OCD and related disorders (OCRD).In this dissertation, I explore OCRDs from both phenomic and genomic aspects. I use rich phenotypes from ABCD Study to investigate OCRD comorbidity and relationships with symptom-level data from the child behavioral checklist (CBCL). I also leverage genome-wide association to explore genetic architecture of OCD and related phenotypes, including polygenic risk score (PRS) analysis with tic disorders within ABCD Study and 12 disorders from the Psychiatric Genomics Consortium. I additionally explore copy-number variation (CNV) among neurodevelopmental disorders, specifically focusing on neurodevelopmental disorders including TS and autism spectrum disorder (ASD).Phenomic analysis of psychopathology in ABCD Study has shown hyperinflated rates of psychiatric disorders in the ABCD Study, likely due to self-endorsement bias. To circumvent that, I define a narrow diagnosis construct that utilizes longitudinal data to refine psychiatric diagnoses. Narrow OCD (nOCD) better reflected childhood OCD prevalence rates and comorbidity patters, and a stronger relationship with symptom-level data from CBCL. Genomic assessment of nOCD has also shown stronger PRS relationship with OCD symptoms compared to broad OCD. Similar effects were also observed in PRS analysis with 12 PGC disorders. CNV analysis of TS has resulted in successful replication of TS-risk contribution by NRXN1 deletions and CNTN6 duplications, as well as identification of 39 additional genes that could potentially contribute to TS pathology. However, genome-wide burdens of CNV numbers or sizes were not replicated.Deconvoluting genetic and phenomic relationships and underpinnings of OCRDs is a complicated task confounded primarily by low sample sizes and suboptimal methodologies. Thus, increased recruitment efforts and improvements to statistical and computational methodologies to analyze these data will likely be the main drivers of discoveries in the OCRD genomics space.