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

Published online by Cambridge University Press:  28 November 2013

A. Hargreaves ,
R. Anney ,
C. O'Dushlaine ,
K. K. Nicodemus ,
M. Gill ,
A. Corvin ,
D. Morris ,
Gary Donohoe ,
Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ)  and
Wellcome Trust Case Control Consortium 2
A. Hargreaves
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
R. Anney
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
C. O'Dushlaine
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
K. K. Nicodemus
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
M. Gill
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
A. Corvin
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
D. Morris
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
Gary Donohoe*
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland School of Psychology, National University of Ireland, Galway, Republic of Ireland
*
*Address for correspondence: Professor G. Donohoe, National University of Ireland, Galway, Republic of Ireland. (Email: donoghug@tcd.ie)
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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.

Keywords

Cell adhesion moleculescognitiongeneHLA-DQA1pathwaypsychosisschizophrenia
Type
Original Articles
Information
Psychological Medicine , Volume 44 , Issue 10 , July 2014 , pp. 2177 - 2187
Copyright
Copyright © Cambridge University Press 2013 

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