May 19, 2011 — A study led by scientists at the Washington University School of Medicine, Saint Louis, Missouri, shows genomewide significant linkage between a region on chromosome 3 and major depressive disorder in individuals with a history of heavy smoking.
An independent study at King's College London, United Kingdom, has also identified this region — 3p25–3p26 — as being linked to severe depression. Both reports were published online May 15 in the American Journal of Psychiatry.
Replicated findings in separate studies of depression are unusual in the genetic linkage literature and in genomewide association studies (GWAS). The new studies provide "one of the strongest replicated genetic findings in studies for depression," said the British paper.
The US study stemmed from an interest in the high incidence of depression among cigarette smokers. Genetic factors are widely acknowledged in depression, but major depression is estimated to occur at some time in the lives of more than 60% of smokers who try to quit. Smokers with this history often experience more difficult nicotine withdrawal and are more likely to resume smoking.
Study participants were selected from families with a history of cigarette smoking and at least 1 pair of siblings having a history of major depression. Both depressive disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and tobacco use and dependency were evaluated by telephone interviews.
Participants (91 Australian families, 187 participants; and 25 Finnish families, 33 participants) were genotyped, and analysis of "affected sibling pair nonparametric linkage" generated logarithmic odds ratio (LOD) scores. Typically, a LOD score greater than 3.0 is evidence of linkage. If LOD equals 3, the odds are 1000 to 1 (ie, 103 to 1) that the linkage is not caused by chance.
"I don't think linkage necessarily provides an advantage over association studies [GWAS], they are just different approaches," explained first author Michele L. Pergadia, PhD, from the Department of Psychiatry, Washington University School of Medicine, in an email to Medscape Medical News.
"Linkage is a classic way to map very broad genomic regions in families that are characterized by specific traits," said Dr. Pergadia. "[I]t highlights an area that may be of interest to study further, in order to identify the actual genes, but it is not a method for identification of the specific genes yet, just a first step in that process."
Analysis of the Australian cohort found a "multipoint LOD score" equaling 4.14 for major depressive disorder in a region on chromosome 3, a result that has genomewide significance (P = .004).
The highest LOD score for a single-point marker was 3.7 for a location within GRM7, the gene for the metabotropic glutamate receptor 7.
The Finnish sample showed no regions with this level of significance, and major linkage signals did not overlap between the Australian and Finnish samples. However, when the US scientists sought to replicate their results, the British researchers contacted them to report the same significant finding, says the Washington University press release.
Authors of the US study note that previous investigators have found evidence of associations between GRM7 variants and depressive disorder, but none of this evidence has reached genomewide significance.
"GRM7 is an interesting gene," observed Douglas F. Levinson, MD, professor of psychiatry, Stanford University School of Medicine, California, in an email to Medscape Medical News. "If you search in PubMed for GRM7 and mood or depression, you will find a large animal pharmacological literature that suggests a role in mood regulation and interest in this gene as a possible antidepressant target."
Dr. Levinson had coauthored a study that suggested a possible GWAS signal in GRM7, but after genomewide correction, the results were not statistically significant. In fact, he is unaware of any significant evidence of associations for GRM7 after correction.
"Our linkage findings highlight a broad area, which spans many genes (>90) that could potentially be contributing to our findings," said Dr. Pergadia. "There are many interesting candidate genes in this region, including, for example, those that code for proteins related to the oxytocin receptor gene (OXTR) [or] GABA transporters (eg, SLC6A11), in addition to those associated with glutamate receptors (eg, GRM7 and GRIP2), but again we did not find any that met genomewide significance.
"So far as I know, while suggestive association has been reported, none of these genes has been associated with depression at the level which would meet genomewide significance (eg, ~5 × 10−8)," Dr. Pergadia added.
The King's College London study investigated recurrent depression, rather than nicotine use, studying sibling pairs with recurrent unipolar depression from clinics in several countries. Their study involved genomewide linkage analysis of 839 families, including 971 pairs of siblings affected with recurrent severe depression.
Their highest LOD scores found were 4.01, for "severe recurrent and very severe recurrent" depression, which identified a linkage signal with genomewide significance in the 3p25-3p26 region. However, when this region was mapped in a depression GWAS sample, the association did not achieve significance. Among potential candidate genes within the region are GRM7 and OXTR, as well as ITPR1 — encoding a receptor for inositol triphosphate, which influences calcium channels and serves as a second messenger in the nervous system.
Despite the replicated findings of these 2 studies, a gene or genes responsible for severe depression are still not identified. Dr. Pergadia summarized the current situation: "I think we're just beginning to make our way through the maze of influences on depression."
The Pergadia study was supported by the European Union and a Center for Inherited Disease Research grant. Various authors in the Pergadia study report receiving an Academy of Finland postdoctoral fellowship, an Australian National Health and Medical Research Council fellowship, the National Health and Medical Research Council (Australia) Sidney Sax Fellowship, and an Australian National Health and Medical Research Council fellowship, as well as funding from the Doctoral Programs of Public Health, University of Helsinki; National Institutes of Health; US Department of Defense; Netherlands Organisation for Scientific Research; Australian National Health and Medical Research Council; AstraZeneca; Genentech; Pfizer; and the Academy of Finland Center of Excellence for Complex Disease Genetics, in addition to receiving an advisory panel payment from AstraZeneca, consultation fees and an unrestricted grant from Pfizer. The Breen study was supported by GlaxoSmithKline Research and Development. Authors in the Breen study report having been employed by GlaxoSmithKline, being a shareholder with GlaxoSmithKline, being an employee and a shareholder with F. Hoffman-La Roche, being affiliated with Medical Genetics, being employed by NeuroSearch A/S, and having received travel and subsistence from GlaxoSmithKline. Dr. Levinson has disclosed no relevant financial relationships.
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