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Overlapping Alcohol Dependence, Major Depression Risk Locus Detected

NEW YORK (GenomeWeb) – A variant in a neuronal patterning-related gene called SEMA3A, which codes for semaphorin 3A, appears to influence susceptibility to both alcohol dependence and major depression in individuals of African American descent, according to new research from a Yale University- and University of Pennsylvania-led team.

As they reported online today in JAMA Psychiatry, the researchers did a genome-wide association study that involved thousands of individuals with African American or European American ancestry who were enrolled in a drug and alcohol dependence study spearheaded by Yale and UPenn between early 1999 and January 2015. By incorporating interview-based diagnostic clues related to alcohol dependence and major depression, they identified a SEMA3A SNP with significant ties to both conditions in the African American participants.

More broadly, the GWAS results suggests that alcohol dependence and major depression overlap genetically to some extent, with some cases potentially stemming from one or a few variants impacting both conditions, corresponding author Joel Gelernter, a psychiatry and human genetics researcher at Yale, and his co-authors noted.

Because alcohol dependence and major depression often go hand-in-hand, the investigators reasoned that there may be overlapping genetic contributors to both conditions — a possibility that has been proposed but not demonstrated conclusively in past genetic studies.

For their GWAS, the researchers considered SNP profiles for 7,822 individuals genotyped on Illumina HumanOmni1-Quad or HumanCore Exome arrays, including 4,653 individuals of African American descent and 3,169 European American individuals. More than half of the participants — 4,480 individuals — were men and 3,342 were women.

The team also gleaned each individual's alcohol dependence and major depression status from semi-structured interviews informed by version IV of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, a handbook that spells out and standardizes diagnostic features for a range of conditions.

Almost 85 percent of the individuals fit at least one of the alcohol dependence or major depression criterion, the researchers noted. And by scrutinizing genotypes for individuals who appeared to have both conditions, they saw over-representation of a variant called rs139438618, in a SEMA3A intron, in the African American individuals with alcohol dependence and major depression comorbidity.

The team's analyses suggest it is tenuously associated with alcohol dependence or major depression alone, but had significant associations when considering both conditions in the African American population. That variant was not significantly associated with the conditions in the European American individuals.

In an accompanying editorial, Virginia Commonwealth University researcher Alexis Edwards noted that SEMA3A "is involved in neuronal patterning, although precisely how variation in the gene affects risk for [alcohol use disorder] and [major depressive disorder] is unclear."

While Edwards lauded the team for "progress toward elucidating which genetic factors increase risk" for comorbid alcohol use disorder and major depressive disorder, she noted that its power for detecting associations was diminished in the ancestry-specific arm of the study — a caution that the authors themselves raised.

"Further efforts to elucidate the molecular risk factors and the causal mechanisms for comorbid [alcohol dependence] and [major depression] will require larger samples to enable a focus on lower-frequency and rare variants that may have large effects," Gelernter and colleagues concluded.