Searching for the Puerperal Trigger: Molecular Genetic Studies of Bipolar Affective Puerperal Psychosis

Ian Jones, MRCPsych, PhD; Nick Craddock, MRCPsych, PhD

Disclosures

Psychopharmacol Bull. 2007;40(2):115-128. 

In This Article

Abstract and Introduction

The available evidence suggests that the puerperium is a period of increased risk for acute episodes of illness in bipolar (BP) women and points to genetic factors as influencing vulnerability to postpartum triggering of such episodes. We have previously reported compelling evidence of familiality of vulnerability to puerperal episodes in female sibs with BP disorder and find similar familial clustering for episodes of narrowly defined postpartum episodes in siblings with major depression. Molecular genetic approaches hold out the promise of uncovering the nature of the puerperal trigger leading to important improvements in the prevention and treatment of postpartum affective episodes. A research strategy focusing on positional and candidate gene approaches may prove fruitful in the search for susceptibility genes for both postpartum triggering in particular and for the affective disorder diathesis in general. We have identified the subset of families in the Wellcome Trust UK-Irish BP sib-pair molecular genetic linkage genome screen that include at least one female who has suffered an episode of puerperal psychosis. Analysis of this more homogeneous subgroup of families resulted in a genome-wide significant linkage signal (LOD = 4.07) on chromosome 16p13 and genome wide suggestive linkage on chromosome 8q24. We are undertaking association studies in women with postpartum psychosis at a number of candidate genes of interest in BP disorder with an emphasis on those for which the expression is influenced by steroid hormones.

The evidence of family, twin, and adoption studies consistently and compellingly points to the importance of genetic factors in susceptibility to bipolar (BP) disorder.[1,2] Families in which a single gene plays a major role are rare and plausible models for the majority of BP disorder postulate more complex mechanisms such as multiple genes of modest effect interacting with each other and with a variety of environmental factors to influence susceptibility.[3] Molecular genetic approaches have made finding BP disorder susceptibility genes possible and in recent years a number of interesting findings are emerging.[4] However, findings vary between studies, almost certainly reflecting variation in clinical and genetic characteristics of samples as well as stochastic factors. It is unclear, at the time of writing, which of the potential BP disorder susceptibility genes will receive wide replication and become established as a true positive although the data for the DAOA (G72) locus on chromosome 13q looks to be a robust finding with at least three published positive reports.[5,6,7]

For complex genetic disorders there are marked benefits in focusing on a clinical homogenous subtype—both to increase phenotypic and genetic homogeneity and to allow a specific subset of hypotheses to be tested.[8] In the case of BP disorder a number of clinical subtypes have been investigated in molecular genetic studies, including rapid cycling illness[9] and lithium responsiveness.[10] In this paper we will focus on a clinical subtype of BP disorder that we believe has a great potential in molecular genetic studies—bipolar affective puerperal psychosis. We will first discuss the evidence linking puerperal psychosis and BP disorder, move on to consider studies implicating genes in the triggering of puerperal episodes, and finish with a brief discussion of molecular genetic approaches to the investigation of this disorder.

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