Dopamine genetic risk score predicts depressive symptoms in healthy adults and adults with depression.
BACKGROUND
Depression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression.


METHODS
Data were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3).


RESULTS
In the discovery sample, the genetic risk score was associated with depressive symptomatology (β = -0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = -0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = -0.86, p = 0.15).


CONCLUSIONS
Sequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression.
Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America.
Kristin M
KM
Pearson-Fuhrhop
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, United States of America; Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Erin C
EC
Dunn
Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America.
Sarah
S
Mortero
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
William J
WJ
Devan
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Guido J
GJ
Falcone
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, United States of America; Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Phil
P
Lee
Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, United States of America; Department of Psychology, Yale University, New Haven, Connecticut, United States of America.
Avram J
AJ
Holmes
Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America.
Marisa O
MO
Hollinshead
Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
Joshua L
JL
Roffman
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, United States of America; Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Jordan W
JW
Smoller
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Jonathan
J
Rosand
Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America; Department of Neurology, University of California Irvine, Irvine, California, United States of America.
Steven C
SC
Cramer
D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003863:Depression / Q000235:genetics* / Q000473:pathology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016014:Linear Models; D010641:Phenotype; D011954:Receptors, Dopamine / Q000235:genetics*; D018570:Risk Assessment / Q000379:methods*
D050483:Dopamine Plasma Membrane Transport Proteins; D011954:Receptors, Dopamine; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase