Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees.
BACKGROUND
We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3-22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for: 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p.


METHODS
Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6. Nonparametric linkage analysis was performed.


RESULTS
Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p =.006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (r =.26; p <.0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p <.0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from.35 to 2.26 on 6p22.2.


CONCLUSIONS
These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia.
Schulze
Thomas G
TG
Genetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Program, Bethesda, USA. schulze@zi-mannheim.de
Buervenich
Silvia
S
Badner
Judith A
JA
Steele
C J M
CJ
Detera-Wadleigh
Sevilla D
SD
Dick
Danielle
D
Foroud
Tatiana
T
Cox
Nancy J
NJ
MacKinnon
Dean F
DF
Potash
James B
JB
Berrettini
Wade H
WH
Byerley
William
W
Coryell
William
W
DePaulo
J Raymond
JR
Gershon
Elliot S
ES
Kelsoe
John R
JR
McInnis
Melvin G
MG
Murphy
Dennis L
DL
Reich
Theodore
T
Scheftner
William
W
Nurnberger
John I
JI
McMahon
Francis J
FJ
D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6; D004843:Epistasis, Genetic; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008297:Male; D009315:National Institute of Mental Health (U.S.); D010375:Pedigree; D011618:Psychotic Disorders / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics; D014481:United States / Q000453:epidemiology