Elsevier

Biological Psychiatry

Volume 60, Issue 2, 15 July 2006, Pages 84-92
Biological Psychiatry

Review
The Genetics of Depression: A Review

https://doi.org/10.1016/j.biopsych.2005.08.024Get rights and content

Major depressive disorder (MDD) is common and moderately heritable. Recurrence and early age at onset characterize cases with the greatest familial risk. Major depressive disorder and the neuroticism personality trait have overlapping genetic susceptibilities. Most genetic studies of MDD have considered a small set of functional polymorphisms relevant to monoaminergic neurotransmission. Meta-analyses suggest small positive associations between the polymorphism in the serotonin transporter promoter region (5-HTTLPR) and bipolar disorder, suicidal behavior, and depression-related personality traits but not yet to MDD itself. This polymorphism might also influence traits related to stress vulnerability. Newer hypotheses of depression neurobiology suggest closer study of genes related to neurotoxic and neuroprotective (neurotrophic) processes and to overactivation of the hypothalamic-pituitary axis, with mixed evidence regarding association of MDD with polymorphisms in one such gene (brain-derived neurotrophic factor [BDNF]). Several genome-wide linkage studies of MDD and related traits have been reported or are near completion. There is some evidence for convergence of linkage findings across studies, but more data are needed to permit meta-analysis. Future directions will include more intensive, systematic study of linkage candidate regions and of the whole genome for genetic association; gene expression array studies; and larger-scale studies of gene-environment interactions and of depression-related endophenotypes.

Section snippets

MDD

The lifetime prevalence of unipolar MDD is at least 10%, with the risk in women twice that in men (Moldin et al 1991, Tsuang et al 1994, Weissman et al 1996). Heritability based on twin studies is 40% to 50% (Bierut et al 1999, Kendler et al 1993a, Kendler et al 2001, McGuffin et al 1991, McGuffin et al 1996, Sullivan et al 2000, Torgersen 1986) and perhaps higher when measurement error is modeled based on repeated assessments (Kendler et al 1993a). Adoption studies provide some support for a

Monoaminergic Candidate Genes and Gene-Environment Interactions

Most of the published genetic association studies of mood disorders have focused on functional polymorphisms (DNA sequence variations that alter the expression and/or functioning of the gene product) in the loci encoding the serotonin transporter (SLC6A4), serotonin 2A receptor (5HTR2A), tyrosine hydroxylase (TH) (the limiting enzyme for dopamine synthesis), tryptophan hydroxylase 1 (TPH1) (serotonin synthesis), and catechol-o-methyltransferase (COMT) (dopamine catabolism). There are one or

Genetic Linkage Studies

An alternative to the study of mechanism-based candidate genes is the positional cloning strategy–the systematic study of the genome, either with genetic linkage studies of informative pedigrees followed by association studies of candidate regions (e.g., using very dense maps of single nucleotide polymorphisms) or systematic genome-wide association studies. The latter have not yet been attempted for depression, but several linkage studies have been or will soon be reported for MDD and related

Future Directions

Depression is a complex and multifactorial trait with important genetic and nongenetic contributory factors. Many methods and strategies will be applied, some of them not yet feasible or even imagined. However, a number of directions can be anticipated which are likely to be fruitful, including (at least) the following.

The positional cloning strategy will certainly be pursued using increasingly powerful methods to scan the genome for regions likely to contain relevant genes and then to search

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