The one and the many: effects of the cell adhesion molecule pathway on neuropsychological function in psychosis

Abstract

Background. Genetic studies of single gene variants have been criticized as providing a simplistic characterization of the genetic basis of illness risk that ignores the effects of other variants within the same biological pathways. Of candidate biological pathways for schizophrenia (SZ), the cell adhesion molecule (CAM) pathway has repeatedly been linked to both psychosis and neurocognitive dysfunction. Here we tested, using risk allele scores derived from the Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), whether alleles within the CAM pathway were correlated with poorer neuropsychological function in patients.Method. In total, 424 patients with psychosis were assessed in areas of cognitive ability typically found to be impaired in SZ: intelligence quotient, memory, working memory and attentional control. CAM pathway genes were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Alleles within these genes identified as significantly associated with SZ risk in the PGC-SCZ were then used to calculate a CAM pathway-based polygenic risk allele score for each patient and these scores were tested for association with cognitive ability.Results. Increased CAM pathway polygenic risk scores were significantly associated with poorer performance on measures of memory and attention, explaining 1-3% of variation on these measures. Notably, the most strongly associated single nucleotide polymorphism (SNP) in the CAM pathway (rs9272105 within HLA-DQA1) explained a similar amount of variance in attentional control, but not memory, as the polygenic risk analysis.Conclusions. These data support a role for the CAM pathway in cognitive function, both at the level of individual SNPs and the wider pathway. In so doing these data highlight the value of pathway-based polygenic risk score studies as well as single gene studies for understanding SZ-associated deficits in cognition.

Effects of MiR‐137 genetic risk score on brain volume and cortical measures in patients with schizophrenia and controls

“…This interplay of SZ risk genes is important to study, given the polygenic nature of the disorder. To characterize the phenotypic effects of multiple risk variants we and others have used polygenic risk scores calculated for gene sets based on either their involvement in a known biological pathway (Hargreaves et al, ), or based on evidence of their being regulated by target risk genes, for example, ZNF804A (Nicodemus et al, ); MIR137 (Cosgrove et al, ). In these studies, similar effects on cognitive function have been observed by studying either the risk variant individually or the gene network with which it interacts, although the network based analysis can sometimes explain a slightly higher percentage of variation (Cosgrove et al, ).…”

Reduced cortical thickness related to single nucleotide polymorphisms in the major histocompatibility complex region in antipsychotic‐naive schizophrenia

“…Hence, polymorphisms of rs1635 could alter the function of the NKAPL protein and thereby influence cortical development. The third SNP, rs9272105, is located approximately 5 kbs upstream of the coding gene HLA‐DQA1 , which is one of the most common cell adhesion molecule (CAM)‐related genes (Hargreaves et al, ). This SNP may alter early human cortical development by up‐ or downregulating neutral‐CAM ( NCAM ) (Cox et al, ).…”

Results and promises of genetics of cognitive impairment in schizophrenia: molecular-genetic approaches

“…Однако в основном эффекты изученных генов оказались малы, а ассоциации плохо воспроизводимы. Кроме того, «кандидатный» подход подвергся критике за некоторую упрощенность, поскольку когнитивные признаки являются полигенными и определяются аддитивными (суммарные) и эпистатическими (отражающие взаимовлияние) эффектами большого количества генов с малым вкладом в вариативность признака [17]. Наконец, «кандидатный» подход ограничен рамками существующих представлений о патогенезе шизофрении и не позволяет выявить принципиально новые гены, участвующие в развитии заболевания.…”