Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease.
We developed and implemented software for the analysis of genome-wide association studies in the context of biological pathway enrichment and have here applied our algorithm to the study of Alzheimer disease (AD). Using genome-wide association data in a large French population, we observed a highly significant enrichment of genes involved in intracellular protein transmembrane transport, including several mitochondrial proteins and nucleoporins. An intriguing aspect of these findings is the implication that TOMM40, the channel-forming subunit of the translocase of the mitochondrial outer membrane complex, and a gene generally considered to be indiscernible from APOE because of linkage disequilibrium, may itself contribute to Alzheimer pathology. Results provide an indication that protein trafficking, in particular across the nuclear and mitochondrial membranes, may contribute to risk for AD.
Hong
Mun-Gwan
MG
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Alexeyenko
Andrey
A
Lambert
Jean-Charles
JC
Amouyel
Philippe
P
Prince
Jonathan A
JA
D000465:Algorithms; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D005602:France / Q000453:epidemiology; D005819:Genetic Markers; D016678:Genome; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D026901:Membrane Transport Proteins / Q000235:genetics*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport / Q000235:genetics*; D012307:Risk Factors; D012984:Software
D001057:Apolipoproteins E; D005819:Genetic Markers; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D028861:Nuclear Pore Complex Proteins; C400783:TOMM40 protein, human