NEW YORK – A UK-led team has tracked down very rare genetic variants with ties to schizophrenia, particularly cases marked by reduced cognitive function.
"The findings of this study suggest that [ultrarare coding variants] contribute to variance in cognitive function in schizophrenia, with partly independent association before and after onset of the disorder," co-senior and co-corresponding authors Michael Owen and Michael O'Donovan, researchers affiliated with Cardiff University's MRC Centre for Neuropsychiatric Genetics and Genomics, and their colleagues wrote in JAMA Psychiatry on Wednesday.
For their study, the investigators searched through protein-coding sequence representing 802 individuals with schizophrenia who underwent exome sequencing at the Broad Institute or Cardiff University, searching for variants that coincided with outcomes on cognition and reading tests. They did not include participants with documented cases of intellectual disability or cognition-related neurological conditions.
"Schizophrenia is typically first diagnosed when psychosis becomes manifest, usually in late adolescence or early adulthood, but premorbid impairments in cognition frequently occur," the authors explained, noting that results from prior studies "are consistent with the hypothesis that rare coding variants may be associated with a higher risk of cognitive impairment in schizophrenia, although no study to date has investigated this in individuals with schizophrenia who have undergone quantitative assessment of cognitive function."
Indeed, the team found that the presence of ultrarare variants in genes that are normally impervious to change, or under selective constraint, coincided with lower-than-usual cognition scores compared with the cases that did not have such ultrarare, constrained variants.
The 400 ultrarare, constrained variants detected in the study were overrepresented in schizophrenia patients with reduced scores on the cognition or IQ tests done before their schizophrenia diagnoses, the researchers said, noting that the genetic factors linked to these features so far together appear to explain more than 6 percent of the cognition variation identified and more than 10 percent of pre-diagnosis IQ variance.
"[A]lthough [ultrarare coding variants] are by definition uncommon, it may be possible to use them to identify a small subgroup of individuals with early signs of schizophrenia or with increased risk of schizophrenia, who are at higher risk of subsequent cognitive decline and in whom early remedial or preventative measures can be implemented," the authors suggested, adding that "rare risk alleles associated with cognitive decline might also help to implicate areas of biology that are important in the impairments in cognitive function that are seen more generally in schizophrenia and which affect functional outcomes."
Though the authors cautioned that the predicted impact of these variants appeared to be relatively subtle, they speculated that "future studies may show that the effect sizes will be greater with better annotation of pathogenic variants."
Moreover, they suggested that genomic profiling may ultimately help to find individuals with schizophrenia who are particularly prone to cognitive impairment "in whom early remedial or preventive measures can be implemented."
In a related JAMA Psychiatry editorial, Tim Bigdeli with SUNY Downstate Health Sciences University and the VA New York Harbor Healthcare System and David Braff at the University of California, San Diego called the study "timely," noting that "because their study participants were cognitively assessed, we are offered a glimpse of how this special class of rare variation affects patients' neurocognition with its association with real-world functioning."
"A time will arrive when [we will] have a comprehensive understanding of schizophrenia genetics — not necessarily of the diagnosis, but rather the quantitative measures related to outcome — and how it relates to patients' real-world functioning," they added. "As we glean additional biological insights, we are duty-bound to prioritize actionable findings, toward realizing some benefit sooner-rather-than-later (and equitably) to patients."