The genetics of early-onset bipolar disorder: A systematic review

Abstract

Background Early-onset bipolar disorder has been associated with a significantly worse prognosis than late-onset BD and has been hypothesized to be a genetically homogenous subset of BD. A sizeable number of studies have investigated early-onset BD through linkage-analyses, candidate-gene association studies, genome-wide association studies (GWAS), and analyses of copy number variants (CNVs), but this literature has not yet been reviewed. Methods A systematic review was conducted using the PubMed database on articles published online before January 15, 2015 and after 1990. Separate searches were made for linkage studies, candidate gene-association studies, GWAS, and studies on CNVs. Results Seventy-three studies were included in our review. There is a lack of robust positive findings on the genetics of early-onset BD in any major molecular genetics method. Limitations Early-onset populations were quite small in some studies. Variance in study methods hindered efforts to interpret results or conduct meta-analysis. Conclusions The field is still at an early phase for research on early-onset BD. The largely null findings mirror the results of most genetics research on BD. Although most studies were underpowered, the null findings could mean that early-onset BD may not be as genetically homogenous as has been hypothesized or even that early-onset BD does not differ genetically from adult-onset BD. Nevertheless, clinically the probabilistic developmental risk trajectories associated with early-onset that may not be primarily genetically determined continued to warrant scrutiny. Future research should dramatically expand sample sizes, use atheoretical research methods like GWAS, and standardize methods.

Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study

“…Although early onset of BD has long been hypothesized to constitute a genetically more homogenous subcategory within the rather heterogenous BD spectrum, the search for phenotype‐specific genetic variants has not yet been successful . Being a highly heritable disorder with 43.2% of its genetic liability being explained by common variants of small effect, the development of BD, similarly to that of other complex polygenic conditions, can be modeled within the framework of a liability‐threshold model .…”

“…This subgroup is associated with a higher recurrence rate of mood episodes, higher rates of psychotic symptoms and of comorbid conditions and more frequent suicide attempts and neurocognitive impairments . Moreover, it has also been hypothesized, mostly based on the observations of family and heritability studies, that early‐onset BD is genetically different from the late‐onset subgroup . However, candidate gene studies and genome‐wide association studies (GWASs) have failed to unambiguously identify genetic markers specifically associated with early‐onset forms of BD.…”

Infectious and immunogenetic factors in bipolar disorder

“…By stratifying genetic data according to more homogeneous phenotypes based on clinical presentation, several studies revealed specific associations, namely with early-onset BD (73). Regarding immunogenetics, the genetic diversity of TLR2, considered to be the most pleiotropic TLR (sensing Gram-positive bacteria, viruses and T. gondii among others), has been explored (74).…”

Solar insolation in springtime influences age of onset of bipolar I disorder

“…Even small changes to circadian rhythms such as the shift to daylight savings time may have adverse mental health consequences . In the future, circadian symptoms and clock gene polymorphisms may help define endophenotypes of bipolar disorder, including early onset .…”