COMMENTARY

Multiple Psych Disorders Genetically Linked -- New Findings

F. Perry Wilson, MD, MSCE

Disclosures

December 12, 2019

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson.

This week, I've been reading this paper appearing in Cell, which described a truly herculean effort to determine some of the genetic underpinnings of psychiatric disorders.

The study begins as a huge genome-wide association study—but man, it has layers. Like an ogre.

Let's start at the top and dig our way in.

Researchers obtained genome data from 232,964 individuals with psychiatric disorders. To put that in context, that's roughly two New Havens' worth of people. The vast majority had major depression, but multiple other psychiatric disorders were also present, as you can see here.


 

They also had four New Havens' worth of controls—nearly 500,000 individuals with genome data. It's crazy big. However, this population wasn't as diverse as real New Haven; all individuals were of self-identified European descent.

But those numbers allowed the researchers to search across the entire genome for small variations in genetic code that were seen much more frequently in those with psychiatric disorders.

All told, they found 136 such hotspots in the genome. That's all the dots above the red line in this Manhattan plot here.


 

That included 35 never-before-reported hotspots, which is pretty incredible. And they could have stopped there, but this is really just the surface of the paper.

The researchers were on the hunt for so-called "pleotropic loci"—hotspots that didn't appear to confer risk for just one psychiatric disorder but for multiple. The idea is that these hotspots would help us begin to understand whether there are common processes central to all psychiatric disease and, of course, to develop more universal treatments.

One hundred and nine hotspots were pleotropic (linked to more than one disorder). Those genomic connections allowed researchers to create this network map, which reveals how these diagnoses are genetically linked.


 

What I find so cool here is how closely this genetically derived map matches what we observe clinically. Bipolar disorder and schizophrenia are strongly linked, as are anorexia nervosa and obsessive-compulsive disorder. The link between autism spectrum disorder and attention-deficit/hyperactivity disorder is no surprise, but some novel findings bear more research, like the genetic link between autism and major depression.

In fact, several different bioinformatic techniques revealed the pattern you see here: three broad groups of disorders, likely representing the sequelae of related genetic processes. Someday, this may redefine how we classify psychiatric disease.

I mentioned the hunt for pleiotropy. Well, one hotspot stood out in this manner above all the rest: a small mutation in a gene called DCC (of colon cancer fame). It was associated with all eight psychiatric diagnoses in the dataset.

This gene is much more than "deleted in colon cancer," though; it guides axonal growth in neurodevelopment.

Germline loss-of-function mutations in DCC cause severe neurodevelopmental syndromes and are often embryonic lethal. We're not talking about a nonfunctioning gene here—just one that is functioning slightly differently, enough to potentially create a brain that is more susceptible to the environmental triggers of psychiatric disorders.

Are drugs targeting DCC going to rid the world of psychiatric disease? Of course not, but the understanding we gain from genetic studies may well redefine how we think of psychiatric disease. And though that may panic the editors of DSM-6, it may benefit our patients in the end.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Program of Applied Translational Research. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @methodsmanmd and hosts a repository of his communication work at www.methodsman.com.

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