WHAT DO WE KNOW ABOUT OFFSPRING AT RISK FOR BIPOLAR DISORDER AND WHAT REMAINS TO BE DISCOVERED

The High Risk paradigm is inherently a genetic epidemiologic study, similar to twin studies, adoption studies, and family studies. The questions posed are: What does the disorder look like before its onset? and What determines the transition between the risk state and onset of illness? These questions relate to the developmental expression of the risk genotype and interactions between risk and resilience.

Many studies have been done using this paradigm in bipolar disorder (BD). The particular sample we have been following comprises 307 young people at risk (first-degree relative of a proband with BD) and 166 controls, followed over the past 15 years. Ascertainment sites in the US are Indiana University School of Medicine, Johns Hopkins University, the University of Michigan and Washington University in St. Louis. We have collaborated with the University of New South Wales in Sydney, Australia. Similar methods of assessment (KSADS-BP and DIGS) have been used in all sites, along with a battery of self-assessment instruments. All participants have provided blood for DNA. All have had GWAS completed and polygenic risk scores calculated and 103 have DNA methylation data. A series of follow-up assessments were carried out over 2007-2020.

Diagnostic outcome is related to polygenic risk (Fullerton et al, 2015 PMID 26178159; Zwicker et al, 2023 PMID 36856707, Freeman et al, unpublished). Polygenic risk interacts with history of trauma to increase the chances of attempted suicide in high-risk offspring (Wilcox et al, 2017 PMID 29173741). Polygenic risk also interacts dramatically with perceived pattern of family interaction (Stapp et al, 2023 PMID 37378048).

Different patterns of comorbidity predicted major mood disorder in high-risk offspring, including both internalizing and externalizing disorders during childhood and early adolescence. These patterns of comorbidity are related to distinct polygenic signatures (Fullerton et al, unpublished).

In the literature, studies focused specifically on the emergence of BD have implicated subthreshold hypomanic/manic symptomatology as a premorbid indicator of developing illness (Hafeman et al, 2017 PMID 28678992). Study of early symptomatic indicators in high-risk offspring have also implicated sleep disorders (Duffy et al, 2019 PMID 30525908) and this may relate to premorbid disruption of circadian rhythms.

Although BD presents clinically as a distinctive syndrome, the genetic predisposition and developmental course of the disorder is complex. Risk for BD may be expressed phenotypically as an internalizing disorder, an externalizing disorder, or a disruption of circadian rhythms. The adult form of the disorder may be unipolar or bipolar, and course and treatment response are influenced by premorbid and comorbid conditions. Brain mechanisms involved are emerging and some of these are described by Drs. Mitchell and Fullerton.