Genetic Predictors of Depressive Symptoms in the Look AHEAD Trial.
OBJECTIVE
Numerous studies have found elevated depressive symptoms among individuals with Type 2 diabetes, yet the mechanisms remain unclear. We examined whether genetic loci previously associated with depressive symptoms predict depressive symptoms among overweight/obese individuals with Type 2 diabetes or change in depressive symptoms during behavioral weight loss.


METHODS
The Illumina CARe iSelect (IBC) chip and Cardiometabochip were characterized in 2118 overweight or obese participants with Type 2 diabetes from Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive life-style intervention and diabetes support and education on cardiovascular morbidity and mortality. Primary analyses focused on baseline Beck Depression Inventory (BDI) scores and depressive symptom change at 1 year.


RESULTS
Of eight single nucleotide polymorphisms (SNPs) in six loci, three a priori SNPs in two loci (chromosome 5: rs60271; LBR: rs2230419, rs1011319) were associated with baseline BDI scores, but in the opposite direction of prior research. In joint analysis of 90,003 IBC and Cardiometabochip SNPs, rs1543654 in the region of KCNE1 predicted change in BDI scores at Year 1 in diabetes support and education (β = -1.05, standard error [SE] = 0.21, p = 6.9 × 10(-7)) at the level of chip-wide significance, while also showing a nominal association with baseline BDI (β = 0.35, SE = 0.16, p = .026). Adjustment for antidepressant medication and/or limiting analyses to non-Hispanic white individuals did not meaningfully alter results.


CONCLUSIONS
Previously reported genetic associations with depressive symptoms did not replicate in this cohort of overweight/obese individuals with Type 2 diabetes. We identified KCNE1 as a potential novel locus associated with depressive symptoms.
From the Weight Control and Diabetes Research Center (McCaffery, Wing), The Miriam Hospital and Warren Alpert School of Medicine at Brown University, Providence, Rhode Island; Center for Statistical Sciences (Papandonatos, Erar), Brown University, Providence, Rhode Island; Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania (Faulconbridge, Wadden), Philadelphia, Pennsylvania; Department of Genetics & Genomic Sciences (Peter), Mount Sinai School of Medicine, New York, New York; Look AHEAD Coordinating Center, Division of Public Health Sciences (Wagenknecht, Anderson), Wake Forest School of Medicine, Winston-Salem, North Carolina; and Department of Biostatistical Sciences (Pajewski), Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Jeanne M
JM
McCaffery
George D
GD
Papandonatos
Lucy F
LF
Faulconbridge
Bahar
B
Erar
Inga
I
Peter
Lynne E
LE
Wagenknecht
Nicholas M
NM
Pajewski
Andrea
A
Anderson
Thomas A
TA
Wadden
Rena R
RR
Wing
D003863:Depression / Q000150:complications / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000523:psychology*; D005006:Ethnicity / Q000235:genetics / Q000523:psychology; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000295:instrumentation; D060005:Genotyping Techniques / Q000295:instrumentation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000523:psychology; D050177:Overweight / Q000150:complications / Q000235:genetics / Q000523:psychology; D020641:Polymorphism, Single Nucleotide; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D015203:Reproducibility of Results; D012720:Severity of Illness Index
C489622:KCNE1 protein, human; D024642:Potassium Channels, Voltage-Gated