Translating Mendelian and complex inheritance of Alzheimer's disease genes for predicting unique personal genome variants

Kelly Regan, Kanix Wang, Emily Doughty, Haiquan Li, Jianrong Li, Younghee Lee, Maricel G. Kann, Yves A. Lussier

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Objective Although trait-associated genes identified as complex versus single-gene inheritance differ substantially in odds ratio, the authors nonetheless posit that their mechanistic concordance can reveal fundamental properties of the genetic architecture, allowing the automated interpretation of unique polymorphisms within a personal genome. Materials and methods An analytical method, SPADEgen, spanning three biological scales was developed to demonstrate the mechanistic concordance between Mendelian and complex inheritance of Alzheimer's disease (AD) genes: biological functions (BP), protein interaction modeling, and protein domain implicated in the disease-associated polymorphism. Results Among Gene Ontology (GO) biological processes (BP) enriched at a false detection rate <5% in 15 AD genes of Mendelian inheritance (Online Mendelian Inheritance in Man) and independently in those of complex inheritance (25 host genes of intragenic AD single-nucleotide polymorphisms confirmed in genomewide association studies), 16 overlapped (empirical p(0.007) and 45 were similar (empirical p<0.009; information theory). SPAN network modeling extended the canonical pathway of AD (KEGG) with 26 new protein interactions (empirical p<0.0001). Discussion The study prioritized new AD-associated biological mechanisms and focused the analysis on previously unreported interactions associated with the biological processes of polymorphisms that affect specific protein domains within characterized AD genes and their direct interactors using (1) concordant GO-BP and (2) domain interactions within STRING protein-protein interactions corresponding to the genomic location of the AD polymorphism (eg, EPHA1, APOE, and CD2AP). Conclusion These results are in line with unique-event polymorphism theory, indicating how disease-associated polymorphisms of Mendelian or complex inheritance relate genetically to those observed as 'unique personal variants'. They also provide insight for identifying novel targets, for repositioning drugs, and for personal therapeutics.

Original languageEnglish (US)
Pages (from-to)306-316
Number of pages11
JournalJournal of the American Medical Informatics Association
Volume19
Issue number2
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Health Informatics

Fingerprint Dive into the research topics of 'Translating Mendelian and complex inheritance of Alzheimer's disease genes for predicting unique personal genome variants'. Together they form a unique fingerprint.

  • Cite this