A new study has pinpointed rare genetic variations that are found more commonly in people with early-onset depression than in people unaffected by the disorder. Many of those variations cluster within gene networks critical to two aspects of neuronal function: calcium signaling and the growth of branched structures called dendrites. The findings, published July 28th in the journal Molecular Psychiatry, suggest that disruptions to these processes may be involved in the development of major depression.

Although genetic factors clearly influence a person's risk of developing major depression, the search for specific genetic variations that contribute to the complex disorder has been slow to yield results.  

Fernando Sampaio Goes, M.D., a 2008 NARSAD Young Investigator at Johns Hopkins School of Medicine, and his colleagues took an alternative approach to the ongoing genome-wide association studies (GWAS) that hunt for these factors by scouring the complete genomes of tens of thousands of individuals. The team––which included 2005 Young Investigator Dimitrios Avramopoulos, M.D., Ph.D.; 2000 Young Investigator, 2008 Independent Investigator, and BBRF Scientific Council member James B. Potash, M.D., M.P.H.; and 2004 Young Investigator Peter P. Zandi, Ph.D.––conceived the study to detect rare genetic variations that GWAS are not designed to find.

Rather than scanning entire genomes for depression-associated variations, Goes's team narrowed its search to a set of genes in which they already suspected alterations might contribute to depression: those that encode proteins found at or near the junctions between neurons, where cell-to-cell communication takes place. Based on previous surveys of these synaptic proteins, the scientists chose 1,742 genes to include in their analysis.

They compared the protein-coding sequences of that set of genes in 259 people with major depression to the same set in 334 unaffected individuals. To increase the chance of finding relevant genetic factors, all the patients with depression were selected based on the criterion of early-onset, recurrent depression, which is suspected by some to be a more heritable form of the illness. (An important component of depression causation is environmental, and reflects the particular life circumstances of those affected, who may or may not be naturally resilient when faced with stress and other environmental factors.)

The team’s analysis pointed to two sets of genes in which variations were linked with major depression. One includes genes that control the growth of dendritic spines (tiny knob-like protrusions from a neuron's surface that receive inputs from other neurons). Other research has suggested that the size, density, and shape of these structures may be involved in mood disorders and other mental illnesses. The second gene set includes genes linked with the entry of calcium into neurons, which regulates a variety of processes, including the release of message-propagating neurotransmitters. Variations within this gene set have also been linked to autism and epilepsy.

Read the abstract.