Huge Genetic Study Reveals Common Threads Across Psychiatric Disorders

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, describing 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 2
New Haven’s worth of people. The vast majority had major depression, but
multiple other psychiatric disorders, as you can see here, were present. They also had 4 New Haven’s worth of controls
– nearly 500,000 individuals with genome data. It’s crazy big. Though 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 dashed 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 just appear to confer risk for one psychiatric
disorder, but for multiple. The idea is that these hotspots would help
us begin to understand if there are common processes central to all psychiatric disease,
and, of course, develop more universal treatments. 109 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 ADHD 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
sequela of related genetic processes. Someday, this may redefine how we classify
psychiatric disease. Now 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 8 psychiatric diagnoses in the dataset. This gene is much more than “deleted in
colon cancer” though – it guides axonal growth in neuro-development. Germline loss-of-function mutations in DCC
cause severe neurodevelopmental syndromes, and are often embryonic lethal – we’re
not talking about a non-functioning 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-VI, it may benefit our patients in the end.

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