Association studies of bipolar disorder

Bipolar Disord. 2001 Dec;3(6):284-98. doi: 10.1034/j.1399-5618.2001.30604.x.


Association studies in outbred populations represent an important paradigm for investigation of complex traits, such as bipolar disorder, both to follow-up regions of interest from linkage studies (by systematic linkage disequilibrium mapping and positional candidate studies) and for pure functional studies. The advantages of the association method include its relative robustness to genetic heterogeneity and the ability to detect much smaller effect sizes than are detectable using feasible sample sizes in linkage studies. The candidate gene approach is potentially very powerful, particularly when used within the context of a VAPSE (variation affecting protein structure or expression) paradigm, but a major problem is that the efficiency in the choice of candidates is inevitably a function of the level of previous understanding of disease pathophysiology. To date, most candidate gene studies in bipolar disorder have focussed on the major neurotransmitter systems that are influenced by medication used in clinical management of the disorder. Early studies often used anonymous markers in the hope of detecting linkage disequilibrium but recently direct examination of polymorphisms of known or presumed functional relevance has become more usual. Most studies in the literature have been of the unrelated case-control design with samples rarely exceeding 200-300 subjects. No definitive findings have yet emerged although there have been some interesting preliminary findings including those with polymorphisms within the genes encoding catechol-o-methyl transferase (COMT), monoamine oxidase A (MAOA) and the serotonin transporter (hSERT; 5-HTT). In this article we critically review the current status of the literature within the context of the important methodological issues and limitations inherent in the use of association studies for genetic dissection of bipolar disorder. We conclude by examining likely future directions and developments in the field.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bipolar Disorder / enzymology
  • Bipolar Disorder / genetics*
  • Carrier Proteins / genetics
  • Humans
  • Linkage Disequilibrium / genetics
  • Membrane Glycoproteins / genetics
  • Membrane Transport Proteins*
  • Minisatellite Repeats
  • Monoamine Oxidase / metabolism
  • Nerve Tissue Proteins*
  • Phenotype
  • Point Mutation / genetics
  • Polymorphism, Genetic / genetics
  • Polymorphism, Restriction Fragment Length
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D3
  • Serotonin Plasma Membrane Transport Proteins
  • Tyrosine 3-Monooxygenase / metabolism


  • Carrier Proteins
  • DRD3 protein, human
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Tyrosine 3-Monooxygenase
  • Monoamine Oxidase