Exome sequencing in obsessive–compulsive disorder reveals a burden of rare damaging coding variants

Halvorsen, Mathew; Samuels, Jack; Wang, Ying; Greenberg, Benjamin D.; Fyer, Abby J.; McCracken, James T.; Geller, Daniel; Knowles, James A.; Zoghbi, Anthony W.; Pottinger, Tess D.; Grados, Marco A.; Riddle, Mark A.; Bienvenu, O. Joseph; Nestadt, Paul S.; Krasnow, Janice; Goes, Fernando S.; Maher, Brion S.; Nestadt, Gerald; Goldstein, David B.

doi:10.1038/s41593-021-00876-8

Cited by 46 publications

(39 citation statements)

References 50 publications

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“…After employing quality control methods, our sample size for burden analysis was 68 anxiety disorder parent‐child trios and 783 control trios. Based on studies of other childhood neuropsychiatric conditions (Cappi et al, 2020; Halvorsen et al, 2021; Satterstrom et al, 2020; S. Wang et al, 2018), we expected to find an enrichment of rare de novo damaging variants, including LGD variants (premature stop codons, frameshift mutations, and splice site variants) and missense variants predicted to be damaging by an MPC score>2 (Mis‐D).…”

Section: Resultsmentioning

confidence: 99%

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Whole‐exome DNA sequencing in childhood anxiety disorders identifies rare de novo damaging coding variants

Olfson

Lebowitz

Hommel

et al. 2022

Depression and Anxiety

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Background: Genetic factors contribute to the development of anxiety disorders, yet few risk genes have been previously identified. One genomic approach that has achieved success in identifying risk genes in related childhood neuropsychiatric conditions is investigations of de novo variants, which has yet to be leveraged in childhood anxiety disorders.Methods: We performed whole-exome DNA sequencing in 76 parent-child trios (68 trios after quality control) recruited from a childhood anxiety disorder clinic and compared rates of rare and ultra-rare de novo variants with 790 previously sequenced control trios (783 trios after quality control). We then explored overlap with risk genes for other neuropsychiatric conditions and enrichment in biologic pathways.Results: Rare and ultra-rare de novo likely gene disrupting and predicted damaging missense genetic variants are enriched in anxiety disorder probands compared with controls (rare variant rate ratio 1.97, 95% confidence interval [CI]: 1.11-3.34, p = .03; ultra-rare variant rate ratio 2.59, 95% CI: 1.35-4.70, p = .008). These de novo damaging variants occur in individuals with a variety of childhood anxiety disorders and impact genes that have been associated with other neuropsychiatric conditions.Exploratory network analyses reveal enrichment of deleterious variants in canonical biological pathways.Conclusions: These findings provide a path for identifying risk genes and promising biologic pathways in childhood anxiety disorders by de novo genetic variant detection. Our results suggest the discovery potential of applying this approach in larger anxiety disorder cohorts to advance our understanding of the underlying biology of these common and debilitating conditions.

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Section: Resultsmentioning

confidence: 99%

“…| 479 (Cappi et al, 2020;Halvorsen et al, 2021). This provides evidence that DNA sequencing studies focused on childhood anxiety disorders have the potential to identify novel high-confidence risk genes.…”

Section: Discussionmentioning

confidence: 95%

Whole‐exome DNA sequencing in childhood anxiety disorders identifies rare de novo damaging coding variants

Olfson

Lebowitz

Hommel

et al. 2022

Depression and Anxiety

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“…The authors identified two high-confidence risk genes, CHD8 and SCUBE1 . Just recently, Halvorsen et al ( 75 ) conducted exome sequencing aiming to identify rare damaging coding variants that could influence the occurrence of OCD. In case–control analyses, the most significant result was observed in SLITRK5 gene.…”

Section: Rare Variants In Ocdmentioning

confidence: 99%

Genomics of Obsessive-Compulsive Disorder—Toward Personalized Medicine in the Era of Big Data

et al. 2021

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Pathogenesis of obsessive-compulsive disorder (OCD) mainly involves dysregulation of serotonergic neurotransmission, but a number of other factors are involved. Genetic underprints of OCD fall under the category of “common disease common variant hypothesis,” that suggests that if a disease that is heritable is common in the population (a prevalence >1–5%), then the genetic contributors—specific variations in the genetic code—will also be common in the population. Therefore, the genetic contribution in OCD is believed to come from multiple genes simultaneously and it is considered a polygenic disorder. Genomics offers a number of advanced tools to determine causal relationship between the exposure and the outcome of interest. Particularly, methods such as polygenic risk score (PRS) or Mendelian Randomization (MR) enable investigation of new pathways involved in OCD pathogenesis. This premise is also facilitated by the existence of publicly available databases that include vast study samples. Examples include population-based studies such as UK Biobank, China Kadoorie Biobank, Qatar Biobank, All of US Program sponsored by National Institute of Health or Generations launched by Yale University, as well as disease-specific databases, that include patients with OCD and co-existing pathologies, with the following examples: Psychiatric Genomics Consortium (PGC), ENIGMA OCD, The International OCD Foundation Genetics Collaborative (IOCDF-GC) or OCD Collaborative Genetic Association Study. The aim of this review is to present a comprehensive overview of the available Big Data resources for the study of OCD pathogenesis in the context of genomics and demonstrate that OCD should be considered a disorder which requires the approaches offered by personalized medicine.

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“…With the recent advances in genetic testing and next-generation sequencing, ultrarare mutations in many forms of neuromuscular diseases have been identified in single families. 4,5 To improve the robustness of genetic diagnosis in these cases, identification of additional families with mutations in the same gene exhibiting similar or overlapping clinical features is required. We previously identified the first case of loss of function variant in GOLGA2 in a single consanguineous family.…”

Section: Introductionmentioning

confidence: 99%

Bi‐allelic loss of function variants in GOLGA2 are associated with a complex neurological phenotype: Report of a second family

Kotecha¹,

Mistri²,

Shah

et al. 2021

Clinical Genetics

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GOGLA2/GM130 is a Golgin protein involved in vesicle tethering, cell proliferation and autophagy. Recessive loss of function mutation in GOLGA2 has been previously reported in a single family with muscular dystrophy and microcephaly. Here we describe a second consanguineous family with the bi-allelic loss of function mutations in GOLGA2. The patient exhibits microcephaly, seizures, and myopathy similar to the previously reported patient with GOLGA2 mutation. This report supports the critical developmental requirement of GOLGA2 and emphasizes a similar and severe clinical presentation with loss of function mutations in affected patients.

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Exome sequencing in obsessive–compulsive disorder reveals a burden of rare damaging coding variants

Cited by 46 publications

References 50 publications

Whole‐exome DNA sequencing in childhood anxiety disorders identifies rare de novo damaging coding variants

Whole‐exome DNA sequencing in childhood anxiety disorders identifies rare de novo damaging coding variants

Genomics of Obsessive-Compulsive Disorder—Toward Personalized Medicine in the Era of Big Data

Bi‐allelic loss of function variants in GOLGA2 are associated with a complex neurological phenotype: Report of a second family

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