A rare missense variant in RCL1 segregates with depression in extended families.
Depression is the most prevalent psychiatric disorder with a complex and elusive etiology that is moderately heritable. Identification of genes would greatly facilitate the elucidation of the biological mechanisms underlying depression, however, its complex etiology has proved to be a major bottleneck in the identification of its genetic risk factors, especially in genome-wide association-like studies. In this study, we exploit the properties of a genetic isolate and its family-based structure to explore whether relatively rare exonic variants influence the burden of depressive symptoms in families. Using a multistep approach involving linkage and haplotype analyses followed by exome sequencing in the Erasmus Rucphen Family (ERF) study, we identified a rare (minor allele frequency (MAF)=1%) missense c.1114C>T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms (N=2393, βT-allele=2.33, P-value=1 × 10-4) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF. Despite being twice as rare (MAF<0.5%), c.1114C>T showed similar effect and significant association with depressive symptoms in samples from the independent population-based Rotterdam study (N=1604, βT-allele=3.60, P-value=3 × 10-2). A comparison of RCL1 expression in human and mouse brain revealed a striking co-localization of RCL1 with the layer 1 interlaminar subclass of astrocytes found exclusively in higher-order primates. Our findings identify RCL1 as a novel candidate gene for depression and offer insights into mechanisms through which RCL1 may be relevant for depression.
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
N
N
Amin
Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
F M S
FMS
de Vrij
Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
M
M
Baghdadi
Department of Cell Biology, Center for Biomics, Erasmus MC, Rotterdam, The Netherlands.
R W W
RWW
Brouwer
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
J G J
JGJ
van Rooij
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
O
O
Jovanova
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
A G
AG
Uitterlinden
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
A
A
Hofman
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.|Department of Hepatology, University Health Network Toronto Western & General Hospital, Toronto, ON, Canada.
H L A
HLA
Janssen
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.
S
S
Darwish Murad
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
R
R
Kraaij
Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
J
J
Stedehouder
Department of Cell Biology, Center for Biomics, Erasmus MC, Rotterdam, The Netherlands.
M C G N
MCGN
van den Hout
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
J M
JM
Kros
Department of Cell Biology, Center for Biomics, Erasmus MC, Rotterdam, The Netherlands.
W F J
WFJ
van IJcken
Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
H
H
Tiemeier
Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
S A
SA
Kushner
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
C M
CM
van Duijn
D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D003863:Depression / Q000235:genetics*; D003866:Depressive Disorder / Q000235:genetics*; D059472:Exome; D005091:Exons; D005190:Family; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D000073359:Exome Sequencing