Genome-wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study

Abstract

IMPORTANCE The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. OBJECTIVE To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs). DESIGN, SETTING, AND PARTICIPANTS A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis.

Constitutive Genetic Deletion of Hcn1 Increases Alcohol Preference during Adolescence

“…In the amygdala, the Hcn1 gene has been identified as a quantitative trait locus for fear learning [44]. Genome-wide association studies (GWAS) have not previously implicated HCN1 in alcohol use disorders, but other GWAS studies have found that HCN1 is associated conditions like schizophrenia and depression, which are known to be comorbid with AUDs [45]. Medications directed at the HCN channel modulation are currently being developed for seizure activity [46] and may prove useful in treating symptoms associated with AUDs associated with withdrawal-related excitability.…”

Investigation of gene-gene interactions in cardiac traits and serum fatty acid levels in the LURIC Health Study

“…The results of our study indicate that GCNT1 and its interacting factors may function via fatty acid related pathways, which promote the development of prostate cancer among people who intake higher amount of omega-6 fatty acids. Besides prostate cancer, gene GCNT1 has previously been linked to neural phenotypes, including the cranial width [62] and cognitive measurements [63]. ASTN2, another gene which interacts with GCNT1, also has demonstrated associations with neural phenotypes including attention-deficit/hyperactivity disorder (ADHD) [64,65], autism spectrum disorders (ASD) [65], neuronal development [65,66], and Alzheimer's disease [67].…”

Genetic and environmental risk structure of internalizing psychopathology in youth

“…Viewed as potential intermediate or “endo” phenotypes (Gottesman & Gould, 2003), such trait‐like psychological constructs are as complex as IDs themselves (Flint, Timpson, & Munafo, 2014). Nonetheless, endophenotypes offer potential developmental insights into psychopathology when their latent structure is examined (Kendler & Neale, 2010) and have recently shown promise for dissecting molecular genetic components of mental illness (Greenwood et al, 2019). Early studies support subsets of measures that index shared or specific components of genetic risk for IDs (reviewed in Savage, Sawyers, Roberson‐Nay, & Hettema, 2016).…”