Prior studies have demonstrated that, in both adults and youth, bipolar disorder (BD) is a polygenic illness. However, no studies have examined polygenic risk scores (PRSs) in relation to the longitudinal course of mood symptoms in youth with BD.
Methods:
This study included 246 youth of European ancestry with BD (7–20 years old at intake) from the Course and Outcome of Bipolar Youth study and Centre for Youth Bipolar Disorder. Mood symptom severity was assessed at intake and, for 168 participants, prospectively for a median of 8.7 years. PRSs for BD, schizophrenia (SCZ), major depressive disorder (MDD), and attention-deficit/hyperactivity disorder (ADHD) were constructed using genome-wide summary statistics from independent adult cohorts.
Results:
Higher BD-PRS was significantly associated with lower most severe lifetime depression score at intake (β = −0.14, p = 0.03). Higher SCZ-PRS and MDD-PRS were associated with significantly less time spent in euthymia (SCZ-PRS: β = −0.21, p = 0.02; MDD-PRS: β = −0.22, p = 0.01) and more time with any subsyndromal mood symptoms (i.e., any mania, mixed, or depression symptoms; SCZ-PRS: β = 0.15, p = 0.04; MDD-PRS: β = 0.17, p = 0.01) during follow-up. PRSs for BD and ADHD were not significantly associated with any longitudinal mood variable.
Conclusions:
This exploratory analysis was the first to examine psychiatric PRSs in relation to the prospective course of mood symptoms among youth with BD. Results from the current study can serve to guide future youth BD studies with larger sample sizes on this topic.
Get full access to this article
View all access options for this article.
References
1.
AminoffSR, TesliM, BettellaF, et al.Polygenic risk scores in bipolar disorder subgroups. J Affect Disord, 2015; 183:310–314.
2.
AndlauerTFM, Guzman-ParraJ, StreitF, et al;Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders. Mol Psychiatry, 2021; 26(4):1286–1298.
3.
AxelsonD, BirmaherBJ, BrentD, et al.A preliminary study of the kiddie schedule for affective disorders and schizophrenia for school-age children mania rating scale for children and adolescents. J Child Adolesc Psychopharmacol, 2003; 13(4):463–470.
4.
AxelsonD, BirmaherB, StroberM, et al.Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry, 2006; 63(10):1139–1148.
5.
BarnettJH, SmollerJW. The genetics of bipolar disorder. Neuroscience, 2009; 164(1):331–343.
6.
BauerM, AndreassenOA, GeddesJR, et al.Areas of uncertainties and unmet needs in bipolar disorders: Clinical and research perspectives. Lancet Psychiatry, 2018; 5(11):930–939.
7.
Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Genomic dissection of bipolar disorder and schizophrenia, including 28 Subphenotypes. Cell, 2018; 173(7):1705–1715.e16.
8.
BirmaherB, AxelsonD, GoldsteinB, et al.Four-Year longitudinal course of children and adolescents with bipolar spectrum disorders: The Course and Outcome of Bipolar Youth (COBY) Study. Am J Psychiatry, 2009; 166(7):795–804.
9.
BirmaherB, AxelsonD, StroberM, et al.Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry, 2006; 63(2):175–183.
10.
BirmaherB, HafemanD, MerrankoJ, et al.Role of polygenic risk score in the familial transmission of bipolar disorder in youth. JAMA Psychiatry, 2022; 79(2):160–168.
11.
BoiesS, MéretteC, PaccaletT, et al.Polygenic risk scores distinguish patients from non-affected adult relatives and from normal controls in schizophrenia and bipolar disorder multi-affected kindreds. Am J Med Genet B Neuropsychiatr Genet, 2018; 177(3):329–336; doi: 10.1002/ajmg.b.32614
12.
ChambersWJ, Puig-AntichJ, HirschM, et al.The assessment of affective disorders in children and adolescents by semistructured interview. Test-retest reliability of the schedule for affective disorders and Schizophrenia for school-age children, present episode version. Arch Gen Psychiatry, 1985; 42(7):696–702.
13.
CharneyAW, RuderferDM, StahlEA, et al.Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Transl Psychiatry, 2017; 7(1):e993.
14.
Cross-Disorder Group of the Psychiatric Genomics Consortium, LeeSH, RipkeS, et al.Genetic relationship between five psychiatric disorders estimated from genome-Wide SNPs. Nat Genet, 2013; 45(9):984–994.
15.
DemontisD, WaltersGB, AthanasiadisG, et al;iPSYCH-Broad Consortium. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nat Genet, 2023; 55(2):198–208.
16.
FaraoneSV, GlattSJ, TsuangMT. The genetics of pediatric-onset bipolar disorder. Biol Psychiatry, 2003; 53(11):970–977.
17.
FullertonJM, KollerDL, EdenbergHJ, et al;Bipolar High Risk Study Group, BiGS Consortium. Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young at-risk individuals. Am J Med Genet B Neuropsychiatr Genet, 2015; 168(7):617–629.
18.
GeT, ChenC-Y, NiY, et al.Polygenic prediction via bayesian regression and continuous shrinkage priors. Nat Commun, 2019; 10(1):1776.
19.
GoldsteinBI, BirmaherB, CarlsonGA, et al.The international society for bipolar disorders task force report on pediatric bipolar disorder: Knowledge to date and directions for future research. Bipolar Disord, 2017; 19(7):524–543.
20.
GordovezFJA, McMahonFJ. The genetics of bipolar disorder. Mol Psychiatry, 2020; 25(3):544–559.
21.
GoreFM, BloemPJN, PattonGC, et al.Global burden of disease in young people aged 10-24 years: A systematic analysis. Lancet, 2011; 377(9783):2093–2102.
22.
HafemanD, UherR, MerrankoJ, et al.Polygenic risk score and individual risk prediction of bipolar disorder. Biol Psychiatry, 2023; 93(9):S66–S67.
23.
HasserisS, AlbiñanaC, VilhjalmssonBJ, et al.Polygenic risk and episode polarity among individuals with bipolar disorder. Am J Psychiatry, 2023; 180(3):200–208.
24.
HowardDM, AdamsMJ, ClarkeT-K, et al;Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci, 2019; 22(3):343–352.
25.
JiangX, HolmesC, McVeanG. The impact of age on genetic risk for common diseases. PLoS Genet, 2021; 17(8):e1009723.
26.
JiangX, ZaiCC, DimickMK, et al.Psychiatric polygenic risk scores across youth with bipolar disorder, youth at high risk for bipolar disorder, and controls. J Am Acad Child Adolesc Psychiatry, 2024; 63(11):1149–1157; doi: 10.1016/j.jaac.2023.12.009
27.
JuddLL, AkiskalHS, SchettlerPJ, et al.The long-term natural history of the weekly symptomatic status of Bipolar I disorder. Arch Gen Psychiatry, 2002; 59(6):530–537.
28.
KachuriL, ChatterjeeN, HirboJ, et al;Polygenic Risk Methods in Diverse Populations (PRIMED) Consortium Methods Working Group. Principles and methods for transferring polygenic risk scores across global populations. Nat Rev Genet, 2024; 25(1):8–25.
29.
KarthikeyanS, DimickMK, FiksenbaumL, et al.Inflammatory markers, brain-derived neurotrophic factor, and the symptomatic course of adolescent bipolar disorder: A prospective repeated-measures study. Brain Behav Immun, 2022; 100:278–286.
30.
KaufmanJ, BirmaherB, BrentD, et al.Schedule for affective disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Initial reliability and validity data. J Am Acad Child Adolesc Psychiatry, 1997; 36(7):980–988.
31.
KellerMB, LavoriPW, FriedmanB, et al.The longitudinal interval follow-up evaluation. a comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry, 1987; 44(6):540–548.
32.
LeverichGS, PostRM, KeckPEJr, et al.The poor prognosis of childhood-onset bipolar disorder. J Pediatr, 2007; 150(5):485–490.
33.
LewisCM, VassosE. Polygenic risk scores: From research tools to clinical instruments. Genome Med, 2020; 12(1):44.
34.
MarangoniC, De ChiaraL, FaeddaGL. Bipolar disorder and ADHD: Comorbidity and diagnostic distinctions. Curr Psychiatry Rep, 2015; 17(8):604.
35.
MartinAR, KanaiM, KamataniY, et al.Clinical use of current polygenic risk scores may exacerbate health disparities. Nat Genet, 2019; 51(4):584–591.
36.
McKnightRF, BilderbeckAC, MiklowitzDJ, et al.Longitudinal mood monitoring in bipolar disorder: Course of illness as revealed through a short messaging service. J Affect Disord, 2017; 223:139–145.
37.
MistryS, Escott-PriceV, FlorioAD, et al.Genetic risk for bipolar disorder and psychopathology from childhood to early adulthood. J Affect Disord, 2019; 246:633–639.
38.
MullinsN, ForstnerAJ, O’ConnellKS, et al;HUNT All-In Psychiatry. Genome-Wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet, 2021; 53(6):817–829.
39.
OwenMJ, WilliamsNM. Explaining the missing heritability of psychiatric disorders. World Psychiatry, 2021; 20(2):294–295.
40.
PetersonRE, KuchenbaeckerK, WaltersRK, et al.Genome-Wide association studies in ancestrally diverse populations: Opportunities, methods, pitfalls, and recommendations. Cell, 2019; 179(3):589–603.
41.
Polygenic Risk Score Task Force of the International Common Disease Alliance, AdeyemoA, BalaconisMK, et al.Responsible use of polygenic risk scores in the clinic: Potential benefits, risks and gaps. Nat Med, 2021; 27(11):1876–1884.
42.
PowerRA, SteinbergS, BjornsdottirG, et al.Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. Nat Neurosci, 2015; 18(7):953–955.
43.
RichardsAL, CardnoA, HaroldG, et al.Genetic liabilities differentiating bipolar disorder, schizophrenia, and major depressive disorder, and phenotypic heterogeneity in bipolar disorder. JAMA Psychiatry, 2022; 79(10):1032–1039.
44.
RuanY, LinY-F, FengY-CA, et al;Stanley Global Asia Initiatives. Improving polygenic prediction in ancestrally diverse populations. Nat Genet, 2022; 54(5):573–580.
45.
RuderferDM, FanousAH, RipkeS, et al;Cross-Disorder Working Group of the Psychiatric Genomics Consortium. Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and Schizophrenia. Mol Psychiatry, 2014; 19(9):1017–1024.
46.
TrubetskoyV, PardiñasAF, QiT, et al;Schizophrenia Working Group of the Psychiatric Genomics Consortium. Mapping genomic loci implicates genes and synaptic biology in Schizophrenia. Nature, 2022; 604(7906):502–508.
47.
Van MeterA, MoreiraALR, YoungstromE. Updated meta-analysis of epidemiologic studies of pediatric bipolar disorder. J Clin Psychiatry, 2019; 80(3); doi: 10.4088/JCP.18r12180
48.
VöhringerPA, PerlisRH. Discriminating between bipolar disorder and major depressive disorder. Psychiatr Clin North Am, 2016; 39(1):1–10.
49.
WarshawMG, DyckI, AllsworthJ, et al.Maintaining reliability in a long-term psychiatric study: An ongoing inter-rater reliability monitoring program using the longitudinal interval follow-up evaluation. J Psychiatr Res, 2001; 35(5):297–305.
50.
WisteA, RobinsonEB, MilaneschiY, et al.Bipolar polygenic loading and bipolar spectrum features in major depressive disorder. Bipolar Disord, 2014; 16(6):608–616.
51.
WrayNR, LinT, AustinJ, et al.From basic science to clinical application of polygenic risk scores: A primer. JAMA Psychiatry, 2021; 78(1):101–109.
52.
YamadaY, MatsumotoM, IijimaK, et al.Specificity and continuity of Schizophrenia and bipolar disorder: Relation to biomarkers. Curr Pharm Des, 2020; 26(2):191–200.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
