Dissecting the genetic heterogeneity of depression through age at onset.
Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom. robert.r.power@kcl.ac.uk
Robert A
RA
Power
Robert
R
Keers
Mandy Y
MY
Ng
Amy W
AW
Butler
Rudolf
R
Uher
Sarah
S
Cohen-Woods
Marcus
M
Ising
Nick
N
Craddock
Michael J
MJ
Owen
Ania
A
Korszun
Lisa
L
Jones
Ian
I
Jones
Michael
M
Gill
John P
JP
Rice
Joanna
J
Hauser
Neven
N
Henigsberg
Wolfgang
W
Maier
Astrid
A
Zobel
Ole
O
Mors
Anna S
AS
Placentino
Marcella
M
Rietschel
Daniel
D
Souery
Dejan
D
Kozel
Martin
M
Preisig
Susanne
S
Lucae
Elisabeth B
EB
Binder
Katherine J
KJ
Aitchison
Federica
F
Tozzi
Pierandrea
P
Muglia
Gerome
G
Breen
Ian W
IW
Craig
Anne E
AE
Farmer
Bertram
B
Müller-Myhsok
Peter
P
McGuffin
Cathryn M
CM
Lewis
D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000453:epidemiology* / Q000235:genetics* / Q000523:psychology; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide