Abstract
Background:Cognitive impairment cuts across traditional diagnostic boundaries and is one of the most typical symptoms in various psychiatric and neurobiological disorders.Aims:The objective of this study was to examine the genetic association between 94 candidate genes, including receptors and enzymes that participate in neurotransmission, with measures of cognition.Methods:The Clinical Dementia Rating (CDR), a global measure of cognition, and genotypes derived from a custom array of 1,536 single-nucleotide polymorphisms (SNPs) in 94 genes were available for a large postmortem cohort of Caucasian cases with Alzheimer’s disease (AD), schizophrenia and controls (n=727). A cohort of healthy young males (n=1,493) originating from the LOGOS project (Learning On Genetics Of Schizophrenia Spectrum) profiled across multiple cognitive domains was available for targeted SNP genotyping. Gene expression was quantified in the superior temporal gyrus of control samples (n=109). The regulatory effect on transcriptional activity was assessed using the luciferase reporter system.Results:The rs5326-A allele at the promoter region of dopamine receptor D1 (DRD1) locus was associated with: (i) poorer cognition (higher CDR) in the postmortem cohort (P=9.325×10−4); (ii) worse cognitive performance relevant to strategic planning in the LOGOS cohort (P=0.008); (iii) lower DRD1 gene expression in the superior temporal gyrus of controls (P=0.038); and (iv) decreased transcriptional activity in human neuroblastoma (SH-SY5Y) cells (P=0.026).Conclusions:An interdisciplinary approach combining genetics with cognitive and molecular neuroscience provided a possible mechanistic link among DRD1 and alterations in cognitive performance.
Highlights
Cognitive impairment is one of the most prevalent symptoms associated with various psychiatric and neurobiological disorders, including schizophrenia and Alzheimer’s disease (AD).[1]
Compared with the reference rs5326 G allele, Association of Consortium on the Genetics of Schizophrenia (COGS) single-nucleotide polymorphisms (SNPs) with Clinical Dementia Rating (CDR) in postmortem cohort The association of COGS SNPs with CDR was examined across all groups using a the A variant was associated with decreased transcriptional activity in human neuroblastoma (SH-SY5Y) cells (20%; P = 0.026; Figure 2c)
We initially performed a targeted genetic analysis in a clinically and neuropathologically characterized postmortem cohort, using an informative panel of SNPs positioned within genes that affect and regulate synaptic transmission (COGS SNP array).[6]
Summary
Cognitive impairment is one of the most prevalent symptoms associated with various psychiatric and neurobiological disorders, including schizophrenia and Alzheimer’s disease (AD).[1]. METHODS: The Clinical Dementia Rating (CDR), a global measure of cognition, and genotypes derived from a custom array of 1,536 single-nucleotide polymorphisms (SNPs) in 94 genes were available for a large postmortem cohort of Caucasian cases with Alzheimer’s disease (AD), schizophrenia and controls (n = 727). RESULTS: The rs5326-A allele at the promoter region of dopamine receptor D1 (DRD1) locus was associated with: (i) poorer cognition (higher CDR) in the postmortem cohort (P = 9.325 × 10 − 4); (ii) worse cognitive performance relevant to strategic planning in the LOGOS cohort (P = 0.008); (iii) lower DRD1 gene expression in the superior temporal gyrus of controls (P = 0.038); and (iv) decreased transcriptional activity in human neuroblastoma (SH-SY5Y) cells (P = 0.026). CONCLUSIONS: An interdisciplinary approach combining genetics with cognitive and molecular neuroscience provided a possible mechanistic link among DRD1 and alterations in cognitive performance
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