Genetics of bipolar disorder

Abstract

Bipolar disorder (also known as manic depressive illness) is a complex genetic disorder in which the core feature is pathological disturbance in mood (aVect) ranging from extreme elation, or mania, to severe depression usually accompanied by disturbances in thinking and behaviour. The lifetime prevalence of 1% is similar in males and females and family, twin, and adoption studies provide robust evidence for a major genetic contribution to risk. There are methodological impediments to precise quantification, but the approximate lifetime risk of bipolar disorder in relatives of a bipolar proband are: monozygotic co-twin 40-70%; first degree relative 5-10%; unrelated person 0.5-1.5%. Occasional families may exist in which a single gene plays the major role in determining susceptibility, but the majority of bipolar disorder involves the interaction of multiple genes (epistasis) or more complex genetic mechanisms (such as dynamic mutation or imprinting). Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of bipolar disorder. No gene has yet been identified but promising findings are emerging. Regions of interest identified in linkage studies include 4p16, 12q23-q24, 16p13, 21q22, and Xq24-q26. Chromosome 18 is also of interest but the findings are confusing with up to three possible regions implicated. To date most candidate gene studies have focused on neurotransmitter systems influenced by medication used in clinical management of the disorder but no robust positive findings have yet emerged. It is, however, almost certain that over the next few years bipolar susceptibility genes will be identified. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. This is likely to lead to major improvements in treatment and patient care but will also raise important ethical issues that will need to be addressed. (J Med Genet 1999;36:585-594)

Candidate risk genes for bipolar disorder are highly conserved during evolution and highly interconnected

“…Follow‐up studies with larger samples confirmed some of the associations and found new candidate risk alleles 18 . As a general observation, these studies suggested that many risk variants of small individual effect size contribute to liability for BPD 9,19 . Depending on the nature of the risk genes identified and molecular pathways involved (see Ref.…”

“…The lifetime prevalence rate is in the range 1%‐3% of the population for the bipolar spectrum disorders 1,6,7 . Although the full pathogenesis remains unclear, genetic factors contribute substantially to the predisposition for developing symptoms 8–10 . Heritability is high and is estimated in the range 60%‐85% 11,12 .…”

Genetic risk for bipolar disorder and schizophrenia predicts structure and function of the ventromedial prefrontal cortex

“…Volumes were acquired with a repetition time of 2.5 s, an echo time of 40 ms, a field of view of 24.3 cm and a flip angle of 85° (total duration 7.5 min). The first 4 (dummy) volumes of each run were discarded to allow for T 1…”

“…Bipolar disorder is a highly heritable 1 and severe psychiatric disorder characterized by recurrent episodes of (hypo)mania and depression. 2 Psychotic symptoms similar to those seen in schizophrenia are commonly observed during manic epi sodes and, consistent with their overlapping diagnostic cri teria and symptoms, 3 bipolar disorder and schizophrenia share at least half of their genetic risk.…”

Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

“…Recently, induced pluripotent stem cell (iPSC) technology has provided encouraging results for the study of neuropsychiatric disorders that result from a combination of pathological changes and compensatory mechanisms [40]. BD is an ideal case for examination in the context of iPSC technology, given its high heritability (up to 85%) [3,41].…”