DNA study untangles the genes underpinning obsessive-compulsive disorder

Obsessive-compulsive disorder is a stigmatized and little-understood mental health condition. People with OCD are often reduced by popular culture to neurotic caricatures, repeatedly seen washing their hands. There’s rarely any larger discussion of the intrusive thoughts, anxiety, and other features of the condition that interfere with daily life. But just as pop culture is missing the point, so too are scientists lacking in information to help understand, diagnose, and treat OCD — but a new study offers some light.

What’s new — A study published this week in the journal Science Advances expands our collective understanding of OCD by shedding light on its genetic underpinnings.

The study, conducted in families where a child has OCD but the parents don’t, reveals how rare, de novo genetic mutations in four genes may tip a person toward an OCD diagnosis. A de novo mutation is a genetic mutation that occurs for the first time in a child’s genes, or in the egg or sperm. In other words, the parents don’t carry this mutation.

Song and his colleagues performed whole-genome sequencing on 53 families — specifically the parents without the diagnosis and their children with the diagnosis — and found four de novo mutations linked to OCD. The mutations are all related to chromatin loops, which are critical to regulating transcription, in which the code of the DNA is written into actual protein in cells.

“These mutations are highly relevant to OCD pathology,” Weichen Song says. Song is a co-author on the new study and a researcher at the Shanghai Jiao Tong University.

Why it matters — The genes pinpointed in this study are also associated with other mental health conditions that can come hand-in-hand with OCD, including anxiety, depression, and anorexia.

This discovery brings us a little closer to understanding the link between genetic mutations and OCD. While this finding doesn’t bring any definitive conclusions, its importance lies in helping illuminate how OCD develops.

“In previous genetic studies of OCD, researchers mainly focus on neurotransmitter genes that directly control brain functions,” Song explains. “Our finding showed that chromatin modification is also an important player, although it is not directly linked to neuronal functions.”

Ultimately, identifying these risk genes may help researchers both diagnose OCD more precisely and may one day lead to drugs that target these genes.

Digging into the details —To the researchers’ knowledge, this is the first time whole-genome sequencing was performed to identify rare de novo variants and changes to genes in families whose children have OCD. Fifty-two of the families were two parents, neither affected by OCD, with one child affected. In one case, there were two unaffected parents with two affected children.

Specifically, the de novo mutations occurred at a higher proportion in parts of genes called promotor-anchored chromatin loops. Chromatin loops are critical to regulating gene transcription, in which the code of the DNA is written into actual protein in cells. They also found de novo mutations in regions associated with distinct gene transcription states, called histone marks.

“Our analysis using public brain RNA data showed that chromatin modification genes could indirectly regulate neurotransmitter genes, and this regulation is disturbed in the brain of OCD patients,” Song explains.

The genes are:

• KDM3B
• ASXL3
• SETD5
• FBL

These are all protein-coding genes, so if there’s an anomaly with chromatin binding, then this gene can’t properly transcribe proteins. While it’s important to note how mutations can alter how proteins are transcribed, this study also underscores the importance of chromatin modification as a potential cause of OCD.

What’s next — As critical as this study is for continuing to investigate OCD, it opens up a world of questions on which other neurodevelopmental disorders are affected by chromatin mechanisms. Little by little, we get closer to understanding this sometimes debilitating, often misunderstood condition.

In Song’s case, his team has used both mice models and cellular models to try and tease out how two genes — SETD5 and KDM3 — may influence behavior.

“These experiments help us better understand what will be the consequence of the disruption of SETD5 and KDM3B in the central nervous system,” he says.

“We also try to find the pathways and networks that SETD5 and KDM3B make their impact on OCD, and the targets that could be inhibited by chemicals would be the potential drug target for future OCD drug discovery.”

Abstract: Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder with a substantial genetic basis and a broadly undiscovered etiology. Recent studies of de novo mutation (DNM) exome-sequencing studies for OCD have reinforced the hypothesis that rare variation contributes to the risk. We performed, to our knowledge, the first whole-genome sequencing on 53 parent-offspring families with offspring affected with OCD to investigate all rare de novo variants and insertions/deletions. We observed higher mutation rates in promoter-anchored chromatin loops (empirical P = 0.0015) and regions with high frequencies of histone marks (empirical P = 0.0001). Mutations affecting coding regions were significantly enriched within coexpression modules of genes involved in chromatin modification during human brain development. Four genes—SETD5, KDM3B, ASXL3, and FBL—had strong aggregated evidence and functionally converged on transcription’s epigenetic regulation, suggesting an important OCD risk mechanism. Our data characterized different genome-wide DNMs and highlighted the contribution of chromatin modification in the etiology of OCD.