Endophenotypes in schizophrenia: A selective review

Abstract

Background Given the wealth of data in the literature on schizophrenia endophenotypes, it is useful to have one source to reference their frequency data. We reviewed the literature on disease-liability associated variants in structural and functional magnetic resonance images (MRI), sensory processing measures, neuromotor abilities, neuropsychological measures, and physical characteristics in schizophrenia patients (SCZ), their first-degree relatives (REL), and healthy controls (HC). The purpose of this review was to provide a summary of the existing data on the most extensively published endophenotypes for schizophrenia. Methods We searched PubMed and MedLine for all studies on schizophrenia endophenotypes comparing SCZ to HC and/or REL to HC groups. Percent abnormal values, generally defined as > 2 SD from the mean (in the direction of abnormality) and/or associated effect sizes (Cohen’s d) were calculated foreach study. Results Combined, the articles reported an average 39.4% (SD=20.7%; range=2.2-100%) of abnormal values in SCZ, 28.1% (SD=16.6%; range=1.6-67.0%) abnormal values in REL, and 10.2% (SD=6.7%; range=0.0-34.6%) in HC groups. Conclusions These findings are reviewed in the context of emerging hypotheses on schizophrenia endophenotypes, as well as a discussion of clustering trends among the various intermediate phenotypes. In addition, programs for future research are discussed, as instantiated in a few recent large-scale studies on multiple endophenotypes across patients, relatives, and healthy controls.

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

“…Although sensory (P50 suppression) and sensorimotor (PPI) gating are conceptually related and both were parallel suggested as useful endophenotypes of schizophrenia they are not equivalent and usually also not correlated [94,[108][109][110]. However, a recent meta-analysis confirmed that electrophysiological gating measures differentiate best between healthy individuals, relatives of schizophrenia patients and the patients themselves when compared to other proposed endophenotypes such as ventricle size, neurological soft signs or neuropsychological dysfunction [111].…”

COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation

“…40,64,88,93 Continuous Performance Test Association with the illness: Schizophrenia has been consistently associated with impairment in CPT discrimination accuracy and reaction time. 12,40,64,97,98 Heritability: The heritability for d' of the CPT, Identical Pairs version (CPT-IP), has been estimated at around 39% for verbal and 49% for spatial attention. 99 For the X-CPT, the heritability has been reported to vary between 48% and 62%.…”

“…[9][10][11] The COMT Val 158 Met polymorphism may therefore contribute to the risk for schizophrenia by influencing specific neuropsychological impairments and brain structural abnormalities, which have been proposed as endophenotypes for this disorder. 12,13 Endophenotypes are heritable traits that possibly represent a causal link between genes and observable phenotypes.…”

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia

“…According to the "common disease common variant" (CDCV) model, one would expect both common and unique quantitative/heritable traits associated with the above syndromes, regulated by these underlying genes, to provide a good starting point for understanding the etiology of SZ and BP. Because definitions of psychiatric diseases are based on clinical phenomenology and lack biological validity (2, 8) a recent strategy has been to use intermediate phenotypes (9,10) to elucidate quantitative/mechanistic aspects of the underlying disease processes, thereby reducing phenotypic heterogeneity and increasing association power (9,11,12). Various properties of intrinsic networks derived from resting-state functional MRI (RS-fMRI) connectivity are promising putative endophenotypes (4, 13).…”