Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees

Biol Psychiatry. 2004 Jul 1;56(1):18-23. doi: 10.1016/j.biopsych.2004.04.004.


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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Bipolar Disorder / epidemiology
  • Bipolar Disorder / genetics*
  • Chromosomes, Human, Pair 6*
  • Epistasis, Genetic
  • Female
  • Genetic Linkage*
  • Genetic Predisposition to Disease*
  • Humans
  • Lod Score
  • Male
  • National Institute of Mental Health (U.S.)
  • Pedigree
  • Psychotic Disorders / genetics
  • Schizophrenia / genetics
  • United States / epidemiology