Background
While antidepressant treatment response appears to be partially heritable, no consistent
genetic associations have been identified. Large, rare copy number variants (CNVs)
play a role in other neuropsychiatric diseases, so we assessed their association with
treatment-resistant depression (TRD).
Methods
We analyzed data from two genome-wide association studies comprising 1263 Caucasian
patients with major depressive disorder. One was drawn from a large health system
by applying natural language processing to electronic health records (i2b2 cohort).
The second consisted of a multicenter study of sequential antidepressant treatments,
Sequenced Treatment Alternatives to Relieve Depression. The Birdsuite package was
used to identify rare deletions and duplications. Individuals without symptomatic
remission, despite two antidepressant treatment trials, were contrasted with those
who remitted with a first treatment trial.
Results
CNV data were derived for 778 subjects in the i2b2 cohort, including 300 subjects
(37%) with TRD, and 485 subjects in Sequenced Treatment Alternatives to Relieve Depression
cohort, including 152 (31%) with TRD. CNV burden analyses identified modest enrichment
of duplications in cases (empirical p = .04 for duplications of 100–200 kilobase) and a particular deletion region spanning
gene PABPC4L (empirical p = .02, 6 cases: 0 controls). Pathway analysis suggested enrichment of CNVs intersecting
genes regulating actin cytoskeleton. However, none of these associations survived
genome-wide correction.
Conclusions
Contribution of rare CNVs to TRD appears to be modest, individually or in aggregate.
The electronic health record-based methodology demonstrated here should facilitate
collection of larger TRD cohorts necessary to further characterize these effects.
Key Words
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Article info
Publication history
Published online: January 21, 2014
Accepted:
October 26,
2013
Received in revised form:
October 3,
2013
Received:
August 1,
2013
Identification
Copyright
© 2014 Published by Elsevier Inc.
