Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci

Abstract

Background Endophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes. Method We genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11× depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram, electrodermal activity and P300 event-related potential. Results Using single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing. Conclusions The results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which genome-wide association study-identified risk loci affect disorder risk.

A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains

“…We did not find an association between polygenic risk scores for schizophrenia and bipolar disorder and the P300 event related potential. Similarly to this, studies by Hall et al () in a sample of 392 patients with schizophrenia and controls, and Liu et al () including a community‐based sample of over 4,000 individuals, both failed to show associations between the P300 and polygenic score for schizophrenia. Nevertheless, research has suggested that the P300 has a significant genetic component.…”

“…Several studies have shown that such polygenic scores differ between patients and controls, thus providing a useful tool to measure genetic liability to psychosis in independent samples (Bramon, Pirinen, Strange, Lin, & Spencer, ; Derks et al, ; Purcell et al, ; Vassos et al, ). A number of studies have investigated the relationship between endophenotypes and polygenic risk scores for schizophrenia and bipolar disorder (Caseras, Tansey, Foley, & Linden, ; Hall et al, ; Hubbard et al, ; Lencz et al, ; Liu et al, ; McIntosh et al, ; Papiol et al, ; Terwisscha van Scheltinga, Bakker, van Haren, Derks, Buizer‐Voskamp, Boos, et al, ; Terwisscha van Scheltinga, Bakker, van Haren, Derks, Buizer‐Voskamp, Cahn, et al, ; Van der Auwera et al, ; Whalley et al, , , ). However, previous studies used a case‐control design and focused on specific endophenotypes.…”

Proper Conditional Analysis in the Presence of Missing Data Identified Novel Independently Associated Low Frequency Variants in Nicotine Dependence Genes

“…To evaluate the effectiveness of methods in real datasets, we applied our methods to a meta-analysis of seven cohorts with a cigarettes-per-day (CPD) phenotype. Participating studies were the Minnesota Center for Twin and Family Research (MCTFR) [12][13][14], SardiNIA [15], METabolic Syndrome In Men (METSIM) [16], Genes for Good [17], COPDGene with samples of European ancestry [18], Center for Antisocial Drug Dependence (CADD) [19] , and UK Biobank. Summary association statistics from the seven cohorts were generated using RVTESTS [20], and meta-analysis performed using RAREMETAL with the PCBS statistics and other competing approaches.…”

A review of endophenotypes in schizophrenia and autism: The next phase for understanding genetic etiologies

“…Endophenotypes hold enormous promise for the study of psychiatric disorders because they may be used to help identify some of the underlying genetic influences on these disorders. Because endophenotypes are biologically closer to the actual gene expression than are the psychological disorders, they should be advantageous for pinpointing specific genotypes that may be related to the disorders (Liu et al, ; McGue, ). Endophenotypes must be associated with the disorder (Gottesman & Gould, ) and may potentially be one facet of the disorder (El‐Fishawy, ).…”

“…If this is correct, then identifying endophenotypes may not in fact be particularly beneficial for discovering genes related to the actual disorders of interest. One recent study suggested that enormous samples are needed to identify underlying genes causally related to endophenotypes (Liu et al, ). Additionally, correlations between genotypes and endophenotypes are not necessarily indicative of causality (Kendler & Neale, ), and thus we must be careful to consider direction of effects as well as the role of environmental influences as we search for genetic effects on both endophenotypes and psychiatric disorders.…”