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Genome-wide strategies for discovering genetic influences on cognition and cognitive disorders: methodological considerations.

ABSTRACT: Genes play a well-documented role in determining normal cognitive function. This paper focuses on reviewing strategies for the identification of common genetic variation in genes that modulate normal and abnormal cognition with a genome-wide association scan (GWAS). GWASs make it possible to survey the entire genome to discover important but unanticipated genetic influences.The use of a quantitative phenotype in combination with a GWAS provides many advantages over a case-control design, both in power and in physiological understanding of the underlying cognitive processes. We review the major features of this approach, and show how, using a General Linear Model method, the contribution of each Single Nucleotide Polymorphism (SNP) to the phenotype is determined, and adjustments then made for multiple tests. An example of the strategy is presented, in which fMRI measures of cortical inefficiency while performing a working memory task are used as the quantitative phenotype. We estimate power under different effect sizes (10-30%) and variations in allelic frequency for a Quantitative Trait (QT) (10-20%), and compare them to a case-control design with an Odds Ratio (OR) of 1.5, showing how a QT approach is superior to a traditional case-control. In the presented example, this method identifies putative susceptibility genes for schizophrenia which affect prefrontal efficiency and have functions related to cell migration, forebrain development and stress response.The use of QT as phenotypes provide increased statistical power over categorical association approaches and when combined with a GWAS creates a strategy for identification of unanticipated genes that modulate cognitive processes and cognitive disorders.

SUBMITTER: Potkin SG

PROVIDER: S-EPMC3037334 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Genome-wide strategies for discovering genetic influences on cognition and cognitive disorders: methodological considerations.

Potkin Steven G SG Turner Jessica A JA Guffanti Guia G Lakatos Anita A Torri Federica F Keator David B DB Macciardi Fabio F

Cognitive neuropsychiatry 20090101 4-5

<h4>Introduction</h4>Genes play a well-documented role in determining normal cognitive function. This paper focuses on reviewing strategies for the identification of common genetic variation in genes that modulate normal and abnormal cognition with a genome-wide association scan (GWAS). GWASs make it possible to survey the entire genome to discover important but unanticipated genetic influences.<h4>Methods</h4>The use of a quantitative phenotype in combination with a GWAS provides many advantage ...[more]

PMID: 19634037

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Project description:BackgroundMicrodialysis is a technique that can be utilized to sample the interstitial fluid of the central nervous system (CNS), including in primary malignant brain tumors known as gliomas. Gliomas are mainly accessible at the time of surgery, but have rarely been analyzed via interstitial fluid collected via microdialysis. To that end, we obtained an investigational device exemption for high molecular weight catheters (HMW, 100 kDa) and a variable flow rate pump to perform microdialysis at flow rates amenable to an intra-operative setting. We herein report on the lessons and insights obtained during our intra-operative HMW microdialysis trial, both in regard to methodological and analytical considerations.MethodsIntra-operative HMW microdialysis was performed during 15 clinically indicated glioma resections in fourteen patients, across three radiographically diverse regions in each patient. Microdialysates were analyzed via targeted and untargeted metabolomics via ultra-performance liquid chromatography tandem mass spectrometry.ResultsUse of albumin and lactate-containing perfusates impacted subsets of metabolites evaluated via global metabolomics. Additionally, focal delivery of lactate via a lactate-containing perfusate, induced local metabolic changes, suggesting the potential for intra-operative pharmacodynamic studies via reverse microdialysis of candidate drugs. Multiple peri-operatively administered drugs, including levetiracetam, cefazolin, caffeine, mannitol and acetaminophen, could be detected from one microdialysate aliquot representing 10 min worth of intra-operative sampling. Moreover, clinical, radiographic, and methodological considerations for performing intra-operative microdialysis are discussed.ConclusionsIntra-operative HMW microdialysis can feasibly be utilized to sample the live human CNS microenvironment, including both metabolites and drugs, within one surgery. Certain variables, such as perfusate type, must be considered during and after analysis. Trial registration NCT04047264.

Dataset Information

Genome-wide strategies for discovering genetic influences on cognition and cognitive disorders: methodological considerations.

Publications

Genome-wide strategies for discovering genetic influences on cognition and cognitive disorders: methodological considerations.

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