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From phenotype to genotype: an association study of longitudinal phenotypic markers to Alzheimer's disease relevant SNPs.

ABSTRACT: Imaging genetic studies typically focus on identifying single-nucleotide polymorphism (SNP) markers associated with imaging phenotypes. Few studies perform regression of SNP values on phenotypic measures for examining how the SNP values change when phenotypic measures are varied. This alternative approach may have a potential to help us discover important imaging genetic associations from a different perspective. In addition, the imaging markers are often measured over time, and this longitudinal profile may provide increased power for differentiating genotype groups. How to identify the longitudinal phenotypic markers associated to disease sensitive SNPs is an important and challenging research topic.Taking into account the temporal structure of the longitudinal imaging data and the interrelatedness among the SNPs, we propose a novel 'task-correlated longitudinal sparse regression' model to study the association between the phenotypic imaging markers and the genotypes encoded by SNPs. In our new association model, we extend the widely used ?(2,1)-norm for matrices to tensors to jointly select imaging markers that have common effects across all the regression tasks and time points, and meanwhile impose the trace-norm regularization onto the unfolded coefficient tensor to achieve low rank such that the interrelationship among SNPs can be addressed. The effectiveness of our method is demonstrated by both clearly improved prediction performance in empirical evaluations and a compact set of selected imaging predictors relevant to disease sensitive SNPs.Software is publicly available at: http://ranger.uta.edu/%7eheng/Longitudinal/heng@uta.edu or shenli@inpui.edu.

SUBMITTER: Wang H

PROVIDER: S-EPMC3436838 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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From phenotype to genotype: an association study of longitudinal phenotypic markers to Alzheimer's disease relevant SNPs.

Wang Hua H Nie Feiping F Huang Heng H Yan Jingwen J Kim Sungeun S Nho Kwangsik K Risacher Shannon L SL Saykin Andrew J AJ Shen Li L

Bioinformatics (Oxford, England) 20120901 18

<h4>Motivation</h4>Imaging genetic studies typically focus on identifying single-nucleotide polymorphism (SNP) markers associated with imaging phenotypes. Few studies perform regression of SNP values on phenotypic measures for examining how the SNP values change when phenotypic measures are varied. This alternative approach may have a potential to help us discover important imaging genetic associations from a different perspective. In addition, the imaging markers are often measured over time, a ...[more]

PMID: 22962490

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Project description:BACKGROUND:Psychosis is a common phenomenon in Alzheimer's disease (AD). The APOE ?4 allele is the strongest genetic risk factor for the development of AD, but its association with psychosis remains unclear. OBJECTIVE:We investigated the associations between psychosis, subdivided into delusions and hallucinations, as well as APOE ?4 allele on cognitive and functional outcomes. Secondarily, we investigated the associations between APOE ?4, Lewy bodies, and psychosis. METHODS:Data from the National Alzheimer's Coordinating Center (NACC) were used. Nine hundred patients with a confirmed diagnosis of AD based on the NIA-AA Reagan were included in the analysis. Global cognition was assessed using the Mini-Mental State Exam (MMSE) and functional status was assessed using the Functional Activities Questionnaire (FAQ). Psychosis status was determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Factorial design was used to assess the effects of psychosis and APOE ?4, as well as their interaction. RESULTS:Psychosis and the presence of APOE ?4 were both associated with lower MMSE scores, while only psychosis was associated with higher FAQ scores. Furthermore, patients with hallucinations had lower MMSE and higher FAQ scores than patients with only delusions. There was a significant interaction effect between psychosis and APOE ?4 on MMSE scores, with APOE ?4 negatively affecting patients with hallucinations-only psychosis. APOE ?4 was positively associated with the presence of Lewy body pathology, and both were found to be more prevalent in psychotic patients, with a stronger association with hallucinations. CONCLUSION:Psychosis in AD was associated with greater cognitive and functional impairments. Patients with hallucinations-with or without delusions-conferred even greater deficits compared to patients with only delusions. The APOE ?4 allele was associated with worse cognition, especially for patients with hallucination-only psychosis. APOE ?4 may mediate cognitive impairment in the hallucinations phenotype through the development of Lewy bodies. Our findings support that subtypes of psychosis should be evaluated separately.

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Dataset Information

From phenotype to genotype: an association study of longitudinal phenotypic markers to Alzheimer's disease relevant SNPs.

Publications

From phenotype to genotype: an association study of longitudinal phenotypic markers to Alzheimer's disease relevant SNPs.

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