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BMC Medicine

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Open Access 01-12-2022 | Research article

Bidirectional genetic overlap between bipolar disorder and intelligence

Authors: Meng-Yuan Shang, Yong Wu, Chu-Yi Zhang, Hao-Xiang Qi, Qing Zhang, Jin-Hua Huo, Lu Wang, Chuang Wang, Ming Li

Published in: BMC Medicine | Issue 1/2022

Abstract

Background

Bipolar disorder (BD) is a highly heritable psychiatric illness exhibiting substantial correlation with intelligence.

Methods

To investigate the shared genetic signatures between BD and intelligence, we utilized the summary statistics from genome-wide association studies (GWAS) to conduct the bivariate causal mixture model (MiXeR) and conjunctional false discovery rate (conjFDR) analyses. Subsequent expression quantitative trait loci (eQTL) mapping in human brain and enrichment analyses were also performed.

Results

Analysis with MiXeR suggested that approximately 10.3K variants could influence intelligence, among which 7.6K variants were correlated with the risk of BD (Dice: 0.80), and 47% of these variants predicted BD risk and intelligence in consistent allelic directions. The conjFDR analysis identified 37 distinct genomic loci that were jointly associated with BD and intelligence with a conjFDR < 0.01, and 16 loci (43%) had the same directions of allelic effects in both phenotypes. Brain eQTL analyses found that genes affected by the “concordant loci” were distinct from those modulated by the “discordant loci”. Enrichment analyses suggested that genes related to the “concordant loci” were significantly enriched in pathways/phenotypes related with synapses and sleep quality, whereas genes associated with the “discordant loci” were enriched in pathways related to cell adhesion, calcium ion binding, and abnormal emotional phenotypes.

Conclusions

We confirmed the polygenic overlap with mixed directions of allelic effects between BD and intelligence and identified multiple genomic loci and risk genes. This study provides hints for the mesoscopic phenotypes of BD and relevant biological mechanisms, promoting the knowledge of the genetic and phenotypic heterogeneity of BD. The essential value of leveraging intelligence in BD investigations is also highlighted.

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McIntyre RS, Berk M, Brietzke E, Goldstein BI, Lopez-Jaramillo C, Kessing LV, et al. Bipolar disorders. Lancet. 2020;396(10265):1841–56.PubMedCrossRef

Carvalho AF, Firth J, Vieta E. Bipolar disorder. N Engl J Med. 2020;383(1):58–66.PubMedCrossRef

Kieseppa T, Partonen T, Haukka J, Kaprio J, Lonnqvist J. High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry. 2004;161(10):1814–21.PubMedCrossRef

McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry. 2003;60(5):497–502.PubMedCrossRef

Bertelsen A, Harvald B, Hauge M. A Danish twin study of manic-depressive disorders. Br J Psychiatry. 1977;130:330–51.PubMedCrossRef

Gordovez FJA, McMahon FJ. The genetics of bipolar disorder. Mol Psychiatry. 2020;25(3):544–59.PubMedCrossRef

Zhang C, Xiao X, Li T, Li M. Translational genomics and beyond in bipolar disorder. Mol Psychiatry. 2021;26(1):186–202.PubMedCrossRef

Mullins N, Forstner AJ, O'Connell KS, Coombes B, Coleman JRI, Qiao Z, et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet. 2021;53(6):817–29.PubMedPubMedCentralCrossRef

Li M, Li T, Xiao X, Chen J, Hu Z, Fang Y. Phenotypes, mechanisms and therapeutics: insights from bipolar disorder GWAS findings. Mol Psychiatry. 2022;27(7):2927–39.PubMedCrossRef

10.

Glahn DC, Almasy L, Barguil M, Hare E, Peralta JM, Kent JW Jr, et al. Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families. Arch Gen Psychiatry. 2010;67(2):168–77.PubMedPubMedCentralCrossRef

11.

Erk S, Meyer-Lindenberg A, Schmierer P, Mohnke S, Grimm O, Garbusow M, et al. Hippocampal and frontolimbic function as intermediate phenotype for psychosis: evidence from healthy relatives and a common risk variant in CACNA1C. Biol Psychiatry. 2014;76(6):466–75.PubMedCrossRef

12.

Hill SK, Reilly JL, Keefe RS, Gold JM, Bishop JR, Gershon ES, et al. Neuropsychological impairments in schizophrenia and psychotic bipolar disorder: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Am J Psychiatry. 2013;170(11):1275–84.PubMedPubMedCentralCrossRef

13.

Koenen KC, Moffitt TE, Roberts AL, Martin LT, Kubzansky L, Harrington H, et al. Childhood IQ and adult mental disorders: a test of the cognitive reserve hypothesis. Am J Psychiatry. 2009;166(1):50–7.PubMedCrossRef

14.

Smith DJ, Anderson J, Zammit S, Meyer TD, Pell JP, Mackay D. Childhood IQ and risk of bipolar disorder in adulthood: prospective birth cohort study. BJPsych Open. 2015;1(1):74–80.PubMedPubMedCentralCrossRef

15.

Karpinski RI, Kinase Kolb AM, Tetreault NA, Borowski TB. High intelligence: a risk factor for psychological and physiological overexcitabilities. Intelligence. 2018;66:8–23.CrossRef

16.

MacCabe JH, Lambe MP, Cnattingius S, Sham PC, David AS, Reichenberg A, et al. Excellent school performance at age 16 and risk of adult bipolar disorder: national cohort study. Br J Psychiatry. 2010;196(2):109–15.PubMedCrossRef

17.

Gale CR, Batty GD, McIntosh AM, Porteous DJ, Deary IJ, Rasmussen F. Is bipolar disorder more common in highly intelligent people? A cohort study of a million men. Mol Psychiatry. 2013;18(2):190–4.PubMedCrossRef

18.

Bahrami S, Shadrin A, Frei O, O'Connell KS, Bettella F, Krull F, et al. Genetic loci shared between major depression and intelligence with mixed directions of effect. Nat Hum Behav. 2021;5(6):795–801.PubMedPubMedCentralCrossRef

19.

Bahrami S, Hindley G, Winsvold BS, O'Connell KS, Frei O, Shadrin A, et al. Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools. Brain. 2021;145(1):142–53.PubMedCentralCrossRef

20.

Rodevand L, Bahrami S, Frei O, Chu Y, Shadrin A, O'Connell KS, et al. Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes. Transl Psychiatry. 2021;11(1):407.PubMedPubMedCentralCrossRef

21.

Frei O, Holland D, Smeland OB, Shadrin AA, Fan CC, Maeland S, et al. Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation. Nat Commun. 2019;10(1):2417.PubMedPubMedCentralCrossRef

22.

Cheng W, Frei O, van der Meer D, Wang Y, O'Connell KS, Chu Y, et al. Genetic association between schizophrenia and cortical brain surface area and thickness. JAMA Psychiatry. 2021;78(9):1020–30.PubMedCrossRef

23.

Bahrami S, Steen NE, Shadrin A, O'Connell K, Frei O, Bettella F, et al. Shared genetic loci between body mass index and major psychiatric disorders: A genome-wide association study. JAMA Psychiatry. 2020;77(5):503–12.PubMedCrossRef

24.

Pisanu C, Congiu D, Severino G, Ardau R, Chillotti C, Del Zompo M, et al. Investigation of genetic loci shared between bipolar disorder and risk-taking propensity: potential implications for pharmacological interventions. Neuropsychopharmacology. 2021;46(9):1680–92.PubMedPubMedCentralCrossRef

25.

Smeland OB, Bahrami S, Frei O, Shadrin A, O'Connell K, Savage J, et al. Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence. Mol Psychiatry. 2020;25(4):844–53.PubMedCrossRef

26.

Cheng W, van der Meer D, Parker N, Hindley G, O'Connell KS, Wang Y, et al. Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood. Mol Psychiatry. 2022. https://doi.org/10.1038/s41380-41022-01751-z.

27.

Icick R, Shadrin A, Holen B, Karadag N, Lin A, Hindley G, et al. Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings. Neuropsychopharmacology. 2022;47(11):1883–91.PubMedCrossRef

28.

Hindley G, Frei O, Shadrin AA, Cheng W, O'Connell KS, Icick R, et al. Charting the landscape of genetic overlap between mental disorders and related traits beyond genetic correlation. Am J Psychiatry. 2022;179(11):833–43.PubMedCrossRef

29.

Savage JE, Jansen PR, Stringer S, Watanabe K, Bryois J, de Leeuw CA, et al. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nat Genet. 2018;50(7):912–9.PubMedPubMedCentralCrossRef

30.

Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh PR, et al. Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control C, Duncan L et al: An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47(11):1236–41.PubMedPubMedCentralCrossRef

31.

Holland D, Frei O, Desikan R, Fan CC, Shadrin AA, Smeland OB, et al. Beyond SNP heritability: Polygenicity and discoverability of phenotypes estimated with a univariate Gaussian mixture model. PLoS Genet. 2020;16(5):e1008612.PubMedPubMedCentralCrossRef

32.

Andreassen OA, Djurovic S, Thompson WK, Schork AJ, Kendler KS, O'Donovan MC, et al. Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. Am J Hum Genet. 2013;92(2):197–209.PubMedPubMedCentralCrossRef

33.

Andreassen OA, Thompson WK, Schork AJ, Ripke S, Mattingsdal M, Kelsoe JR, et al. Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. PLoS Genet. 2013;9(4):e1003455.PubMedPubMedCentralCrossRef

34.

Wang D, Liu S, Warrell J, Won H, Shi X, Navarro FCP, et al. Comprehensive functional genomic resource and integrative model for the human brain. Science. 2018;362(6420):eaat8464.PubMedPubMedCentralCrossRef

35.

Qi T, Wu Y, Fang H, Zhang F, Liu S, Zeng J, et al. Genetic control of RNA splicing and its distinct role in complex trait variation. Nat Genet. 2022;54(9):1355–63.PubMedPubMedCentralCrossRef

36.

Collado-Torres L, Burke EE, Peterson A, Shin J, Straub RE, Rajpurohit A, et al. Regional heterogeneity in gene expression, regulation, and coherence in the frontal cortex and hippocampus across development and schizophrenia. Neuron. 2019;103(2):203–16.PubMedPubMedCentralCrossRef

37.

GTEx Consortium. Laboratory Data Analysis, Coordinating Center -Analysis Working Group, Statistical Methods groups-Analysis Working Group, Enhancing GTEx groups, NIH Common Fund, Nih/Nci, Nih/Nhgri, Nih/Nimh, Nih/Nida et al: Genetic effects on gene expression across human tissues. Nature. 2017;550(7675):204–13.PubMedCentralCrossRef

38.

O'Brien HE, Hannon E, Hill MJ, Toste CC, Robertson MJ, Morgan JE, et al. Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders. Genome Biol. 2018;19(1):194.PubMedPubMedCentralCrossRef

39.

Walker RL, Ramaswami G, Hartl C, Mancuso N, Gandal MJ, de la Torre-Ubieta L, et al. Genetic control of expression and splicing in developing human brain informs disease mechanisms. Cell. 2019;179(3):750–771 e722.PubMedPubMedCentralCrossRef

40.

Jerber J, Seaton DD, Cuomo ASE, Kumasaka N, Haldane J, Steer J, et al. Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation. Nat Genet. 2021;53(3):304–12.PubMedPubMedCentralCrossRef

41.

Bryois J, Calini D, Macnair W, Foo L, Urich E, Ortmann W, et al. Cell-type-specific cis-eQTLs in eight human brain cell types identify novel risk genes for psychiatric and neurological disorders. Nat Neurosci. 2022;25(8):1104–12.PubMedCrossRef

42.

Gillespie M, Jassal B, Stephan R, Milacic M, Rothfels K, Senff-Ribeiro A, et al. The reactome pathway knowledgebase 2022. Nucleic Acids Res. 2022;50(D1):D687–d692.PubMedCrossRef

43.

UniProt C. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res. 2021;49(D1):D480–9.CrossRef

44.

Kohler S, Gargano M, Matentzoglu N, Carmody LC, Lewis-Smith D, Vasilevsky NA, et al. The Human Phenotype Ontology in 2021. Nucleic Acids Res. 2021;49(D1):D1207–17.PubMedCrossRef

45.

Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605–12.PubMedCrossRef

46.

Bipolar Disorder Schizophrenia Working Group of the Psychiatric Genomics Consortium. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell. 2018;173(7):1705–1715 e1716.CrossRef

47.

Trubetskoy V, Pardinas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604(7906):502–8.PubMedPubMedCentralCrossRef

48.

Edwards SL, Beesley J, French JD, Dunning AM. Beyond GWASs: illuminating the dark road from association to function. Am J Hum Genet. 2013;93(5):779–97.PubMedPubMedCentralCrossRef

49.

Shen SQ, Kim-Han JS, Cheng L, Xu D, Gokcumen O, Hughes AE, et al. A candidate causal variant underlying both higher intelligence and increased risk of bipolar disorder. bioRxiv. 2019:580258.

50.

Perry W, Minassian A, Feifel D, Braff DL. Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania. Biol Psychiatry. 2001;50(6):418–24.PubMedCrossRef

Title: Bidirectional genetic overlap between bipolar disorder and intelligence
Authors: Meng-Yuan Shang
Yong Wu
Chu-Yi Zhang
Hao-Xiang Qi
Qing Zhang
Jin-Hua Huo
Lu Wang
Chuang Wang
Ming Li
Publication date: 01-12-2022
Publisher: BioMed Central
Published in: BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-022-02668-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Bidirectional genetic overlap between bipolar disorder and intelligence

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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