Whole-genome association study of bipolar disorder.
We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the University College London sample collections with successful genotyping for 372,193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P=1.66 x 10(-7)) and tetraspanin-8 (TSPAN8; P=6.11 x 10(-7)). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 x 10(-8), TSPAN8; P=7.57 x 10(-7) and EGFR; P=8.36 x 10(-8)). For replication, we genotyped 304 SNPs in family-based NIMH samples (n=409 trios) and University of Edinburgh case-control samples (n=365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case-Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.
Sklar
P
P
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. sklar@chgr.mgh.harvard.edu
Smoller
J W
JW
Fan
J
J
Ferreira
M A R
MA
Perlis
R H
RH
Chambert
K
K
Nimgaonkar
V L
VL
McQueen
M B
MB
Faraone
S V
SV
Kirby
A
A
de Bakker
P I W
PI
Ogdie
M N
MN
Thase
M E
ME
Sachs
G S
GS
Todd-Brown
K
K
Gabriel
S B
SB
Sougnez
C
C
Gates
C
C
Blumenstiel
B
B
Defelice
M
M
Ardlie
K G
KG
Franklin
J
J
Muir
W J
WJ
McGhee
K A
KA
MacIntyre
D J
DJ
McLean
A
A
VanBeck
M
M
McQuillin
A
A
Bass
N J
NJ
Robinson
M
M
Lawrence
J
J
Anjorin
A
A
Curtis
D
D
Scolnick
E M
EM
Daly
M J
MJ
Blackwood
D H
DH
Gurling
H M
HM
Purcell
S M
SM
D000951:Antigens, Neoplasm / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D066246:ErbB Receptors / Q000235:genetics*; D005787:Gene Frequency; D005819:Genetic Markers; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008487:Medical History Taking; D008562:Membrane Glycoproteins / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics*; D024701:Myosin Type V / Q000235:genetics*; D018579:Patient Selection; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D059470:Tetraspanins
D000951:Antigens, Neoplasm; D005819:Genetic Markers; C505832:MYO5B protein, human; D008562:Membrane Glycoproteins; C065609:TSPAN8 protein, human; D059470:Tetraspanins; D004247:DNA; D066246:ErbB Receptors; D024701:Myosin Type V; D018995:Myosin Heavy Chains