Identification of the Slynar gene (AY070435) and related brain expressed sequences as a candidate gene for susceptibility to affective disorders through allelic and haplotypic association with bipolar disorder on chromosome 12q24.
OBJECTIVE
Three linkage studies of bipolar disorder have implicated chromosome 12q24.3, with significant lod scores of over 3.00. Several other linkage studies have found lod scores between 2.00 and 3.00. In order to identify which gene on this chromosome is responsible, the authors carried out tests of allelic association with bipolar disorder in order to fine map an affective disorder susceptibility gene.


METHODS
DNA samples from 681 bipolar disorder patients and 570 comparison subjects from Denmark and the United Kingdom were genotyped with markers close to the region at which the authors had found maximum linkage in previous studies.


RESULTS
Single marker allelic association was found with four markers in the Danish cohort. Seven markers in exactly the same region were then found to show significant allelic association in the U.K. cohort. Tests of haplotypic association were also significant, confirming the single marker allelic associations.


CONCLUSIONS
These positive fine mapping results validate earlier linkage studies and implicate a 278-kilobase region of chromosome 12 that contributes to the etiology of bipolar disorder. Several brain transcripts are transcribed from sequences in the region. The main candidate gene has no known function but is found in human brain cDNA and is homologous to a Macaque brain cDNA. Sequencing of expressed sequences and control regions in the area should identify etiological base pair changes that increase susceptibility to bipolar disorder.
Kalsi
Gursharan
G
Molecular Psychiatry Laboratory, Windeyer Institute for Medical Science, Department of Psychiatry and Behavioral Sciences, Royal Free and University College Medical School, University College London, 46 Cleveland St., London W1T 4JF, United Kingdom.
McQuillin
Andrew
A
Degn
Birte
B
Lundorf
Mikkel D
MD
Bass
Nicholas J
NJ
Lawrence
Jacob
J
Choudhury
Khalid
K
Puri
Vinay
V
Nyegaard
Mette
M
Curtis
David
D
Mors
Ole
O
Kruse
Torben
T
Kerwin
Simon
S
Gurling
Hugh
H
D000483:Alleles; D001714:Bipolar Disorder / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002874:Chromosome Mapping / Q000706:statistics & numerical data; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D015331:Cohort Studies; D018076:DNA, Complementary / Q000235:genetics; D003718:Denmark / Q000208:ethnology; D015870:Gene Expression; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D018895:Microsatellite Repeats; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom / Q000208:ethnology; D044465:White People / Q000235:genetics
D018076:DNA, Complementary; D005819:Genetic Markers