A genome-wide look at variants in RNA-binding proteins has revealed that such variants were disproportionately linked to the risk of multiple psychiatric disorders.
Variants in RNA-binding proteins themselves, their target proteins, or both affected the risk of each of five major neuropsychiatric diseases -- schizophrenia, bipolar disorder, major depression, autism and attention deficit hyperactivity disorder (ADHD).
The findings, which were published in the January 18, 2021, online issue of Nature Genetics, are the first comprehensive look at possible roles for RNA-binding proteins in neuropsychiatric disease, lead author Christopher Park told BioWorld Science.
Park is a genomics research scientist at the Flatiron Institute, which is the in-house research institute of the Simons Foundation.
"There's been previous studies that looked at RNA-binding proteins and disease, especially with respect to splicing," he said, "But people really haven't done a genome-wide analysis... [they] have looked at individual instances, or have looked at splicing."
Splicing introns out of RNA transcripts is one major role of RNA-binding proteins. Spinraza (nusinersen; Biogen/Ionis Pharmaceuticals) is an antisense oligonucleotide that targets an RNA-binding protein to affect the dysfunctional splicing that underlies spinal muscular atrophy type I.
But RNA-binding proteins have multiple functions across the lifespan. In addition to splicing, they play a role in other post-translational modifications as well as transcript stability, localization and translation. Those roles are especially important in neurons, because synapses, the always-changing connections between neurons that enable the nervous system to function, can be far from the cell body, where translation occurs. The longest axons in the human body measure several feet.
Park, senior author Olga Troyanskaya, and their colleagues suspected that RNA-binding proteins might account for some of the missing heritability of neuropsychiatric disorders.
"A genetic component is large in these neurodevelopmental or neuropsychiatric diseases," Park said. And to cause disease, variants "are going through some biological or biochemical processes."
To understand which variants might be linked to the specific biological process of RNA binding, the team first developed Seqweaver, a computational method that could predict whether a given variant would disrupt the binding of an RNA-binding protein at its target site.
They then used Seqweaver to look at five large genome-wide association study (GWAS) datasets investigating schizophrenia, bipolar disorder, major depression, autism and ADHD.
In each disease, they found that the dysregulation of RNA-binding proteins could explain "a substantial amount of heritability not captured by large-scale molecular quantitative trait loci studies and [had] a stronger impact than common coding region variants," they wrote in their paper. Variants in both RNA-binding proteins and their targets could be associated with disease risk.
The team looked at common inherited variants, with common being defined as present in greater than 5% of the population.
Developing effective therapies for neuropsychiatric diseases has lagged compared with other therapeutic areas. One likely reason is that the diagnostic categories of neuropsychiatric disease are not reflective of the underlying biology. Instead, symptoms and risk variants are often shared between multiple disorders.
Park and his colleagues, however, identified variants in the RNA-binding protein interleukin enhancer-binding factor 3 (ILF3) and its targets as associated with bipolar disorder, but not with schizophrenia. Park hopes to follow up on those differences, but noted that the identification of specific targets was not the main goal of his team's work.
"We are looking at common variants, so... it's only contributing small amounts," he said. Typically, "our study per se is not going to point to a specific site."