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Obsessive Compulsive Disorder Exome Analysis Uncovers Contributions From Rare Coding Variants

NEW YORK – Findings from a new exome sequencing study suggest that rare, damaging variants in protein-coding portions of the genome may contribute to obsessive compulsive disorder risk — an effect that appeared particularly pronounced in males with the neuropsychiatric condition.

For a paper published in Nature Neuroscience on Monday, investigators from the University of North Carolina at Chapel Hill, Johns Hopkins University, Columbia University, and elsewhere sequenced the exomes of more than 1,300 individuals with OCD, searching for rare single nucleotide variants (SNVs) or small insertions and deletions (indels) that distinguished these cases from almost 11,600 unaffected individuals with exome information.

The team described a general overrepresentation of rare variants in the OCD exomes, including a slew of damaging changes to genes that are considered loss-of-function (LOF)-intolerant. The damaging variants turned up particularly often in an inhibitory and excitatory synapse-related gene called SLITRK5, and in exome sequences from males in affected parent-child trios.

"Among the results of these analyses, an unexpected observation was that male OCD trio probands carried a higher load of damaging de novo coding SNVs and indels than female OCD trio probands," co-senior authors David Goldstein of Columbia University and Gerald Nestadt, a researcher at Johns Hopkins, and their colleagues wrote.

Past studies have implicated an overrepresentation of rare alterations in autism spectrum disorder, or ASD, and other neuropsychiatric conditions, the team explained. While such variants are suspected of contributing to OCD as well, they have been less fully characterized, despite the apparent heritability gap that remains after genome-wide association studies focused on common variants linked to the condition.

"An excess of rare damaging variation has been detected across multiple studies focused on different psychiatric cohorts," the authors noted. "This study is, to our knowledge, the most comprehensive cataloguing of contributions to OCD risk from rare damaging coding SNVs and indels thus far."

By digging into exome sequence data from sporadic OCD cases in parent-child trios, quartets, or singleton cases from the OCD Genetics Association Study with a series of analyses, the researchers got a look at rare damaging variants in individual genes and across the exome.

Results from the team's gene-collapsing, loss-of-function mutation rate, and de novo mutation analyses on subsets of the cases and controls provided a look at the representation of rare variants in individual genes, including SLITRK5, while examining the extent to which rare, damaging alterations were enriched across the exome and in LOF-intolerant genes.

When it came to de novo SNVs and indels, for example, the investigators found that especially deleterious alterations more often turned up in male patients with OCD — a pattern that was distinct from that previously described in ASD, where damaging de novo alterations have been detected at higher levels in affected females. The de novo mutation analysis also highlighted CHD8 — an ASD- and developmental disorder-associated gene — as a potential contributor to OCD.

Together, the authors noted, these and other findings from the study "suggest that, like the genetic architecture of other neuropsychiatric disorders, OCD involves contributions to overall risk from these variants."

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