Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.
Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
J
J
Song
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
S E
SE
Bergen
National Centre for Mental Health, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
A
A
Di Florio
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
R
R
Karlsson
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
A
A
Charney
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
D M
DM
Ruderfer
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
E A
EA
Stahl
Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
K D
KD
Chambert
Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
J L
JL
Moran
Department of Psychiatry, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
K
K
Gordon-Smith
National Centre for Mental Health, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
L
L
Forty
School of Biomedical and Healthcare Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
E K
EK
Green
National Centre for Mental Health, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
I
I
Jones
Department of Psychiatry, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
L
L
Jones
Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
E M
EM
Scolnick
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
P
P
Sklar
Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
J W
JW
Smoller
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
P
P
Lichtenstein
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
C
C
Hultman
National Centre for Mental Health, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
N
N
Craddock
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
M
M
Landén
Jordan W
JW
Smoller
Roy H
RH
Perlis
Phil Hyoun
PH
Lee
Victor M
VM
Castro
Alison G
AG
Hoffnagle
Pamela
P
Sklar
Eli A
EA
Stahl
Shaun M
SM
Purcell
Douglas M
DM
Ruderfer
Alexander W
AW
Charney
Panos
P
Roussos
Carlos Pato
CP
Michele Pato
Helen
H
Medeiros
Janet
J
Sobel
Nick
N
Craddock
Ian
I
Jones
Liz
L
Forty
Arianna Di
AD
Florio
Elaine
E
Green
Lisa
L
Jones
Katherine
K
Gordon-Smith
Mikael
M
Landen
Christina
C
Hultman
Anders
A
Jureus
Sarah
S
Bergen
Steven
S
McCarroll
Jennifer
J
Moran
Jordan W
JW
Smoller
Kimberly
K
Chambert
Richard A
RA
Belliveau
D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000097:blood; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008094:Lithium / Q000378:metabolism / Q000627:therapeutic use; D018020:Lithium Compounds / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D057566:Self Report; D013548:Sweden; D006113:United Kingdom
D018692:Antimanic Agents; D054316:Biomarkers, Pharmacological; D002352:Carrier Proteins; D018020:Lithium Compounds; C549105:SESTD1 protein, human; D008094:Lithium