Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

Abstract

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

Transcriptome-wide association study reveals two genes that influence mismatch negativity

“…To estimate the utility of MMN to understand more about the genetics of psychosis, we calculated the SNP-based endophenotype ranking value (ERV SNP , a 0-1 scale value representing genetic overlap between phenotype and illness; Glahn et al, 2012) of MMN and 3 comparator phenotypes that have previously been associated with psychosis risk (Thygesen et al, 2020). The results (Figure 3) show that the ERV SNP for MMN (0.28) is substantially higher (there is no overlap between the lower bound of the confidence area and the upper bounds thereof for the other endophenotypes) than those of lateral ventricular volume (LVV; 0.02), Rey Auditory Verbal Learning Task (RAVLT) delayed (0.10), and RAVLT immediate (0.13).…”

“…Psychosis is a highly heritable mental disorder characterized by hallucinations, delusions, and cognitive deficits (American Psychiatric Association, 2013;Bergen et al, 2012;Anttila et al, 2018;Hilker et al, 2018;Thygesen et al, 2020). It has recently been conceptualized as a disorder of aberrant precision-the precision weighting of sensory stimuli is skewed (Limongi et al, 2018).…”

The phenotype of 15 cases with rare 8q24.13‐q24.3 deletions–A new syndrome or still an enigma?

“…In addition, lack of demonstration of the examined variant in large databases of healthy individuals does not necessarily support the pathogenicity of a CNV. For instance, lack of association between rare CNV burden and intellectual quotient has been demonstrated by a recent meta‐analysis, encompassing ten studies with a total of 18,847 participants (Thygesen et al, 2020). The authors aimed to examine the hypothesis that large and rare CNVs are more likely to be pathogenic and exert greater phenotypic effects (Szatkiewicz et al, 2014).…”

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

“…Subtle disturbance of information processing can also be observed in patients' siblings, especially in first-degree relatives [79][80][81][82]. However, cognitive impairment is clearly linked to firmly established common and rare genetic variants conferring risk to schizophrenia [83][84][85][86][87].…”