Role of Polygenic Risk Score in the Familial Transmission of Bipolar Disorder in Youth

Abstract

IMPORTANCEEstablishing genetic contributions to the transmission of bipolar disorder (BD) from parents to offspring may inform the risk of developing this disorder and further serve to validate BD in youth.OBJECTIVE To evaluate the specific association of BD polygenic risk scores (PRSs) on the familial transmission and validity of pediatric BD. DESIGN, SETTING, AND PARTICIPANTS This community-based case-control longitudinal study (Pittsburgh Biological Offspring Study) included parents with BD I/II and their offspring and parents without BD (healthy or non-BD psychopathology) and their offspring. Participants were recruited between March 2001 and May 2007, and analysis took place from December 2020 to September 2021. EXPOSURES PRSs for BD, major depressive disorder, schizophrenia, and attention-deficit/ hyperactivity disorder. MAIN OUTCOMES AND MEASURES Participants were prospectively evaluated using standardized interviews blind to parental diagnosis. DNA was extracted from saliva and genotyped. PRSs were constructed based on independent large-scale genome-wide association studies. RESULTS A total of 156 parents with BD I/II and 180 parents without BD (mean [SD] age, 39.6 [7.9] years; 241 female [72%]) as well as 251 offspring of parents with BD and 158 offspring of parents without BD (mean [SD] age, 10.4 [4.7] years; 213 female [52%]) of European ancestry were analyzed. Participants were assessed a mean of 6.7 times during a mean (SD) of 13 (3.4) years of follow-up (84% retention). More offspring of parents with BD developed BD (58 [23.1%] vs 8 [5.1%]; P < .001) and depression (126 [50.2%] vs 52 [32.9%];P < .001) compared with offspring of parents without BD. BD PRS was higher in both parents and offspring with BD than parents and offspring without BD (parents: odds ratio, 1.50; 95% CI, 1.19-1.89; P < .001; explained 4.8% of the phenotypic variance vs offspring: hazard ratio, 1.34; 95% CI, 1.03-1.7; P = .02; explained 5.0% of the phenotypic variance). BD PRS did not differ across BD subtypes. In a model combining parental and offspring BD PRS, the parental BD PRS association with offspring BD was fully mediated by offspring BD PRS (hazard ratio, 1.40; 95% CI, 1.05-1.86; P = .02). Parental BD had a stronger direct association than parental or offspring BD PRS with offspring BD risk (hazard ratio, 5.21; 95% CI, 1.86-14.62; P = .002), explaining 30% of the variance. Parental and offspring BD PRS explained 6% of the BD onset variance beyond parental diagnosis. There were no significant between-group differences in PRSs for major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder in parents or offspring and they were not significantly associated with BD onset. CONCLUSIONS AND RELEVANCEThe findings of this study add to the extant clinical validation of BD in youth. Parental BD and offspring BD PRS independently associated with the risk of BD in offspring. Although this is promising, the association of BD PRS was relatively small and cannot be used alone to determine BD risk until further...

Annual Research Review. ‘There, the dance is - at the still point of the turning world’: dynamic systems perspectives on co-regulation and dysregulation during early development

“…Another would be to measure caregiver-child interaction across multiple 'static snapshot' assessments (i.e. individual observations, several months apart), and using a technique such as dynamic structural equation modelling, include genetic risk as a covariate by examining specific alleles that contribute to polygenic risk scores for anxiety but which are not shared between children and caregivers (Birmaher et al, 2022). Other approaches are to study special populations, such as caregivers raising genetically unrelated children (Harold et al, 2013), and interventions that specifically target child-caregiver behaviours to examine the long-term development of symptoms in the child (C. G. Smith et al, 2022a).…”

The role of bipolar polygenic risk score in the familial transmission of bipolar disorder—An updated analysis

“…Bipolar disorder (BD) is a highly heritable condition, but the genetic contributions to the transmission of BD from parents to offspring have not been elucidated 1,2 . To evaluate this, polygenic risk scores (PRS), a weighted average of the single nucleotide polymorphisms (SNPs), for BD, major depressive disorder (MDD), Schizophrenia, and attention deficit hyperactive disorder (ADHD) were compared between 156 BD‐I/II parents and their offspring ( n = 251, 10.4 ± 4.7 years at intake) and 180 control parents (healthy or non‐BD psychopathology) and their offspring ( n = 158) of European ancestry 3 . Participants were followed for 13 ± 3.4 years on average 6.7 times.…”

“…1,2 To evaluate this, polygenic risk scores (PRS), a weighted average of the single nucleotide polymorphisms (SNPs), for BD, major depressive disorder (MDD), Schizophrenia, and attention deficit hyperactive disorder (ADHD) were compared between 156 BD-I/II parents and their offspring (n = 251, 10.4 ± 4.7 years at intake) and 180 control parents (healthy or non-BD psychopathology) and their offspring (n = 158) of European ancestry. 3 Participants were followed for 13 ± 3.4 years on average 6.7 times. Both BD parents and their offspring showed significantly higher BD-PRS than their respective controls.…”

A Double-Blind Randomized Trial to Investigate Mechanisms of Antidepressant-Related Dysfunctional Arousal in Depressed or Anxious Youth at Familial Risk for Bipolar Disorder

“…Moreover, when these offspring develop dysfunctional emotional arousal, their risk of developing BD increases even further [ 14 ]. We now also know that multiple genes may moderate the association between having a parent with BD and an offspring’s development of BD [ 15 ], and that even healthy youth who have a parent with BD have distinct prefrontal, striatal, and limbic function and connectivity at rest [ 16 ], and during emotional [ 17 ] and reward processing [ 18 ] compared with healthy offspring of depressed and healthy parents. Taken together, these data suggest that neurogenetic vulnerabilities for developing BD precede symptom onset and may progress to manic symptom emergence and the onset of BD.…”