Modeling gene-by-environment interaction in comorbid depression with alcohol use disorders via an integrated bioinformatics approach

被引:27
作者
McEachin, Richard C. [1 ,2 ]
Keller, Benjamin J. [2 ,3 ]
Saunders, Erika F. H. [1 ]
McInnis, Melvin G. [1 ,2 ]
机构
[1] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Natl Ctr Integrat Biomed Informat, Ann Arbor, MI 48109 USA
[3] Eastern Michigan Univ, Dept Comp Sci, Ypsilanti, MI 48197 USA
关键词
D O I
10.1186/1756-0381-1-2
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Comorbidity of Major Depressive Disorder (depression) and Alcohol Use Disorders (AUD) is well documented. Depression, AUD, and the comorbidity of depression with AUD show evidence of genetic and environmental influences on susceptibility. We used an integrated bioinformatics approach, mining available data in multiple databases, to develop and refine a model of gene-by-environment interaction consistent with this comorbidity. Methods: We established the validity of a genetic model via queries against NCBI databases, identifying and validating TNF (Tumor Necrosis Factor) and MTHFR (Methylenetetrahydrofolate Reductase) as candidate genes. We used the PDG-ACE algorithm (Prioritizing Disease Genes by Analysis of Common Elements) to show that TNF and MTHFR share significant commonality and that this commonality is consistent with a response to environmental exposure to ethanol. Finally, we used MetaCore from GeneGo, Inc. to model a gene-by-environment interaction consistent with the data. Results: TNF Alpha Converting Enzyme (TACE) activity is suppressed by ethanol exposure, resulting in reduced TNF signaling. TNF binds to TNF receptors, initiating signal transduction pathways that activate MTHFR expression. MTHFR is an essential enzyme in folate metabolism and reduced folate levels are associated with both AUD and depression. Integrating these pieces of information our model shows how excessive alcohol use would be expected to lead to reduced TNF signaling, reduced MTHFR expression, and increased susceptibility to depression. Conclusion: The proposed model provides a novel hypothesis on the genetic etiology of comorbid depression with AUD, consistent with established clinical and biochemical data. This analysis also provides an example of how an integrated bioinformatics approach can maximize the use of available biomedical data to improve our understanding of complex disease.
引用
收藏
页数:13
相关论文
共 51 条
[1]   Folic acid and the treatment of depression [J].
Abou-Saleh, Mohammed T. ;
Coppen, Alec .
JOURNAL OF PSYCHOSOMATIC RESEARCH, 2006, 61 (03) :285-287
[2]   THE BIOLOGY OF FOLATE IN DEPRESSION - IMPLICATIONS FOR NUTRITIONAL HYPOTHESES OF THE PSYCHOSES [J].
ABOUSALEH, MT ;
COPPEN, A .
JOURNAL OF PSYCHIATRIC RESEARCH, 1986, 20 (02) :91-101
[3]   SERUM AND RED BLOOD-CELL FOLATE IN DEPRESSION [J].
ABOUSALEH, MT ;
COPPEN, A .
ACTA PSYCHIATRICA SCANDINAVICA, 1989, 80 (01) :78-82
[4]   Ethanol strongly potentiates apoptosis induced by HIV-1 proteins in primary human brain microvascular endothelial cells [J].
Acheampong, E ;
Mukhtar, M ;
Parveen, Z ;
Ngoubilly, N ;
Ahmad, N ;
Patel, C ;
Pomerantz, RJ .
VIROLOGY, 2002, 304 (02) :222-234
[5]   Gene Ontology: tool for the unification of biology [J].
Ashburner, M ;
Ball, CA ;
Blake, JA ;
Botstein, D ;
Butler, H ;
Cherry, JM ;
Davis, AP ;
Dolinski, K ;
Dwight, SS ;
Eppig, JT ;
Harris, MA ;
Hill, DP ;
Issel-Tarver, L ;
Kasarskis, A ;
Lewis, S ;
Matese, JC ;
Richardson, JE ;
Ringwald, M ;
Rubin, GM ;
Sherlock, G .
NATURE GENETICS, 2000, 25 (01) :25-29
[6]   The impact of CYP allelic variation on antidepressant metabolism: a review [J].
Black, John L., III ;
O'Kane, Dennis J. ;
Mrazek, David A. .
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2007, 3 (01) :21-31
[7]   Pharmacogenomics and serotonergic agents: research observations and potential clinical practice implications [J].
Camilleri, M. .
NEUROGASTROENTEROLOGY AND MOTILITY, 2007, 19 :40-45
[8]   Mapping complex disease loci in whole-genome association studies [J].
Carlson, CS ;
Eberle, MA ;
Kruglyak, L ;
Nickerson, DA .
NATURE, 2004, 429 (6990) :446-452
[9]   MAPPING THE DOMAIN(S) CRITICAL FOR THE BINDING OF HUMAN TUMOR-NECROSIS-FACTOR-ALPHA TO ITS 2 RECEPTORS [J].
CHEN, PCH ;
DUBOIS, GC ;
CHEN, MJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (06) :2874-2878
[10]   Determinants of the success of whole-genome association testing [J].
Clark, AG ;
Boerwinkle, E ;
Hixson, J ;
Sing, CF .
GENOME RESEARCH, 2005, 15 (11) :1463-1467