Genetic pathway‐based hierarchical clustering analysis of older adults with cognitive complaints and amnestic mild cognitive impairment using clinical and neuroimaging phenotypes

Abstract

Hierarchical clustering is frequently used for grouping results in expression or haplotype analyses. These methods can elucidate patterns between measures that can then be applied to discerning their validity in discriminating between experimental conditions. Here a hierarchical clustering method is used to analyze the results of an imaging genetics study using multiple brain morphology and cognitive testing endpoints for older adults with amnestic mild cognitive impairment (MCI) or cognitive complaints (CC) compared to healthy controls (HC). The single nucleotide polymorphisms (SNPs) are a subset of those included on a larger array that are found in a reported Alzheimer's disease (AD) and neurodegeneration pathway. The results indicate that genetic models within the endpoints cluster together, while there are 4 distinct sets of SNPs that NIH Public Access Author ManuscriptAm J Med Genet B Neuropsychiatr Genet. Author manuscript; available in PMC 2011 July 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript differentiate between the endpoints, with most significant results associated with morphology endpoints rather than cognitive testing of patients' reported symptoms. The genes found in at least one cluster are ABCB1, APBA1, BACE1, BACE2, BCL2, BCL2L1, CASP7, CHAT, CST3, DRD3, DRD5, IL6, LRP1, NAT1, and PSEN2. The greater associations with morphology endpoints suggests that changes in brain structure can be influenced by an individual's genetic background in the absence of dementia and in some cases (Cognitive Complaints group) even without those effects necessarily being detectable on commonly used clinical tests of cognition. The results are consistent with polygenic influences on early neurodegenerative changes and demonstrate the effectiveness of hierarchical clustering in identifying genetic associations among multiple related phenotypic endpoints.

Genome-wide association study of CSF biomarkers Aβ 1-42 , t-tau, and p-tau 181p in the ADNI cohort

“…A block was created if 95% of informative comparisons were in strong LD. 19 Heat maps and hierarchical clustering 12,20 were employed for visualization of multiple statistical results and selecting important groups of genotypes and phenotypes for further analysis. Table 1 shows the demographic information for the final set of 374 non-Hispanic Caucasian participants and summary statistics for the 5 CSF biomarkers (3 baseline measurements and 2 ratios).…”

Genome-wide pathway analysis of memory impairment in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks

“…There are numerous extant metrics for assessing memory in amnestic populations, and these metrics can have differential sensitivities to various deficits (Lezak 2004). As a result, studies often attempt to leverage the relative strengths and weaknesses of these metrics by creating composite memory scores from multiple assessments given to study participants (Barbeau et al 2011; Sloan et al 2010). In addition, emerging evidence suggests that applying modern psychometric theory to the creation of these composite scores may yield an optimized measure of memory functioning that serves as a more powerful phenotype for genetic studies (see (Crane et al 2011) and the other companion papers in this issue for more detail).…”

An exploratory study of host polymorphisms in genes that clinically characterize breast cancer tumors and pretreatment cognitive performance in breast cancer survivors

“…Moreover, normal breast tissue from women with BC was reported to display higher levels of BCL2 expression than breast tissue from women with no evidence of cancer 79. In relation to neurologic phenotypes, polymorphisms in BCL2 have been found to impact outcomes after traumatic brain injury and have been associated with hippocampal volume 80,81…”