Identifying blood biomarkers for mood disorders using convergent functional genomics

There are to date no objective clinical laboratory blood tests for mood disorders. The current reliance on patient self-report of symptom severity and on the clinicians’ impression is a rate-limiting step in effective treatment and new drug development. We propose, and provide proof of principle for...

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Bibliographic Details
Published in:	Molecular psychiatry Vol. 14; no. 2; pp. 156 - 174
Main Authors:	Le-Niculescu, H, Kurian, S M, Yehyawi, N, Dike, C, Patel, S D, Edenberg, H J, Tsuang, M T, Salomon, D R, Nurnberger, J I, Niculescu, A B
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01.02.2009 Nature Publishing Group
Subjects:	Adult Adult and adolescent clinical studies Affective disorders Aged Animal models Animals Bayes Theorem Bayesian analysis Behavioral Sciences Biological and medical sciences Biological markers Biological Psychology Biomarkers Biomarkers - blood Bipolar disorder Bipolar disorders Brain Brain - metabolism Brain research Case-Control Studies Cohort Studies Diagnosis Drug development Emotional disorders ErbB-3 protein Female Fibroblast growth factor receptor 1 Gene expression Gene Expression - physiology Gene Expression Profiling - methods Genetic aspects Genomes Genomics Genomics - methods Humans Identification and classification Illnesses Insulin-like growth factor-binding protein 4 Insulin-like growth factor-binding protein 6 Intercellular Signaling Peptides and Proteins - blood Intercellular Signaling Peptides and Proteins - genetics Male Medical sciences Medicine Medicine & Public Health Mice Middle Aged Mood Mood disorders Mood Disorders - blood Mood Disorders - classification Mood Disorders - genetics Mood Disorders - pathology Myelin Sheath - genetics Myelin Sheath - metabolism Myelination Neurobiology Neurosciences Oligonucleotide Array Sequence Analysis - methods original-article Peripheral myelin protein 22 Pharmacogenomics Pharmacotherapy Postmortem Changes Predictive Value of Tests Psychiatric research Psychiatry Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Reference Values Reproducibility of Results Signal Transduction - genetics Young Adult United States La Jolla California Indiana United States > US Indianapolis Indiana convergent functional genomics bipolar mood brain blood biomarkers Mood disorder Human Affect affectivity Animal model Methodology Central nervous system Biological marker Bipolar disorder Gene expression Genetic determinism Encephalon Mood Genetics Pharmacogenomics
ISSN:	1359-4184, 1476-5578, 1476-5578
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Summary:	There are to date no objective clinical laboratory blood tests for mood disorders. The current reliance on patient self-report of symptom severity and on the clinicians’ impression is a rate-limiting step in effective treatment and new drug development. We propose, and provide proof of principle for, an approach to help identify blood biomarkers for mood state. We measured whole-genome gene expression differences in blood samples from subjects with bipolar disorder that had low mood vs those that had high mood at the time of the blood draw, and separately, changes in gene expression in brain and blood of a mouse pharmacogenomic model. We then integrated our human blood gene expression data with animal model gene expression data, human genetic linkage/association data and human postmortem brain data, an approach called convergent functional genomics, as a Bayesian strategy for cross-validating and prioritizing findings. Topping our list of candidate blood biomarker genes we have five genes involved in myelination ( Mbp , Edg2 , Mag , Pmp22 and Ugt8 ), and six genes involved in growth factor signaling ( Fgfr1 , Fzd3 , Erbb3 , Igfbp4 , Igfbp6 and Ptprm ). All of these genes have prior evidence of differential expression in human postmortem brains from mood disorder subjects. A predictive score developed based on a panel of 10 top candidate biomarkers (five for high mood and five for low mood) shows sensitivity and specificity for high mood and low mood states, in two independent cohorts. Our studies suggest that blood biomarkers may offer an unexpectedly informative window into brain functioning and disease state.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1359-4184 1476-5578 1476-5578
DOI:	10.1038/mp.2008.11