Lead author Tiffany A. Greenwood, PhD, noted that clinically diverse schizophrenia patients often are grouped together to get large sample sizes for genome-wide association studies, which can miss specific features of the heterogeneous disorder. Instead, in phase 2 of the Consortium on the Genetics of Schizophrenia (COGS) study, Dr. Greenwood and associates sought to connect features clustered into endophenotypes with certain genetic regions of interest.
“As stable biomarkers of the underlying brain dysfunctions, endophenotypes hold promise for parsing clinical heterogeneity of schizophrenia and refining the genetic signal,” they wrote. The study was published in JAMA Psychiatry.
Using this approach among 1,533 participants, they found seven regions exceeding the conventional genome-wide association significance of P less than 5 x 10–8, including regions associated with the endophenotypes of face memory (chromosome 3p21; effect size, –0.72; P = 4.2 x 10–8), antisaccade task (chromosome 9q31; effect size, –0.24; P = 3.5 x 10–8), and abstraction and mental flexibility (chromosome 10q23; effect size, –0.56; P = 1.5 x 10–8).
Those endophenotypes and genes intersect theoretical molecular and biological processes that have been identified in other research and could explain underlying mechanisms of schizophrenia. For example, research has suggested that NRG3, which is near the region associated with abstraction and mental flexibility, and affects certain cellular signaling pathways, could be a locus of susceptibility; in particular, some variants of NRG3 have been associated with cognitive and psychotic symptom severity in previous research.
“Although shared genetic substrates appear likely, this is not a study of schizophrenia but rather a study of neurophysiological and neurocognitive deficits that occur in the general population but are more pronounced in the context of schizophrenia and have implications for treatment,” wrote Dr. Greenwood, of the University of California, San Diego, and associates.
One limitation of the study is that, as investigators have demonstrated elsewhere, P values can prove highly variable over the course of replication studies, so the significance thresholds shown in this study still could run the risk of hiding false positives or negatives.
“As many of the 11 endophenotypes have been endorsed as targets for the development of novel treatments for schizophrenia, a better understanding of the corresponding cellular and molecular processes may pave the way for precision-based medicine in schizophrenia and perhaps other psychiatric illnesses with a shared genetic liability,” Dr. Greenwood and associates concluded.
SOURCE: Greenwood TA et al. JAMA Psychiatry. 2019 Oct 9. doi: 10.1001/jamapsychiatry.2019.2850.