Neuropsychiatric polygenic scores are weak predictors of professional categories

12 min read Original article ↗
  • Hatemi, P. K. et al. Genetic influences on political ideologies: twin analyses of 19 measures of political ideologies from five democracies and genome-wide findings from three populations. Behav. Genet. 44, 282–294 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  • Hatemi, P. K. & McDermott, R. The genetics of politics: discovery, challenges, and progress. Trends Genet. 28, 525–533 (2012).

    Article  CAS  PubMed  Google Scholar 

  • Abdellaoui, A. et al. Genetic correlates of social stratification in Great Britain. Nat. Hum. Behav. 3, 1332–1342 (2019).

    Article  PubMed  Google Scholar 

  • Day, F. R., Ong, K. K. & Perry, J. R. B. Elucidating the genetic basis of social interaction and isolation. Nat. Commun. 9, 2457 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • Okbay, A. et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature 533, 539–542 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, J. J. et al. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat. Genet. 50, 1112–1121 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rietveld, C. A. et al. GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Science 340, 1467–1471 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belsky, D. W. et al. The genetics of success: how single-nucleotide polymorphisms associated with educational attainment relate to life-course development. Psychol. Sci. 27, 957–972 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  • Li, H. et al. Genome-wide association study of creativity reveals genetic overlap with psychiatric disorders, risk tolerance, and risky behaviors. Schizophr. Bull. 46, 1317–1326 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  • Hill, W. D. et al. Genome-wide analysis identifies molecular systems and 149 genetic loci associated with income. Nat. Commun. 10, 5741 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vreeker, A. et al. High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls. Psychol. Med. 46, 807–818 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Bansal, V. et al. Genome-wide association study results for educational attainment aid in identifying genetic heterogeneity of schizophrenia. Nat. Commun. 9, 3078 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dalsgaard, S. et al. Association of mental disorder in childhood and adolescence with subsequent educational achievement. JAMA Psychiatry 77, 797–805 (2020).

    Article  PubMed  Google Scholar 

  • MacCabe, J. H. et al. Artistic creativity and risk for schizophrenia, bipolar disorder and unipolar depression: a Swedish population-based case–control study and sib-pair analysis. Br. J. Psychiatry 212, 370–376 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Parnas, J., Sandsten, K. E., Vestergaard, C. H. & Nordgaard, J. Schizophrenia and bipolar illness in the relatives of university scientists: an epidemiological report on the creativity–psychopathology relationship. Front. Psychiatry 10, 175 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Burstein, D. et al. Genome-wide analysis of a model-derived binge eating disorder phenotype identifies risk loci and implicates iron metabolism. Nat. Genet. 55, 1462–1470 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bigdeli, T. B. et al. Penetrance and pleiotropy of polygenic risk scores for schizophrenia, bipolar disorder, and depression among adults in the US Veterans Affairs health care system. JAMA Psychiatry 79, 1092–1101 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  • Demontis, D. et al. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nat. Genet. 55, 198–208 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheutlin, A. B. et al. Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four health care systems. Am. J. Psychiatry 176, 846–855 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Hingorani, A. D. et al. Performance of polygenic risk scores in screening, prediction, and risk stratification: secondary analysis of data in the Polygenic Score Catalog. BMJ Med 2, e000554 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  • Kyaga, S. et al. Creativity and mental disorder: family study of 300,000 people with severe mental disorder. Br. J. Psychiatry 199, 373–379 (2011).

    Article  PubMed  Google Scholar 

  • Kyaga, S. et al. Mental illness, suicide and creativity: 40-year prospective total population study. J. Psychiatr. Res. 47, 83–90 (2013).

    Article  PubMed  Google Scholar 

  • Power, R. A. et al. Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. Nat. Neurosci. 18, 953–955 (2015).

    Article  CAS  PubMed  Google Scholar 

  • Denny, J. C. et al. Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat. Biotechnol. 31, 1102–1110 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brainstorm Consortiumet al. Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757 (2018).

    Article  Google Scholar 

  • Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379 (2013).

    Article  PubMed Central  Google Scholar 

  • Fuller, T. & Reus, V. Shared genetics of psychiatric disorders. F1000Res. 8, 1626 (2019).

    Article  CAS  Google Scholar 

  • Becker, J. et al. Resource profile and user guide of the Polygenic Index Repository. Nat. Hum. Behav. 5, 1744–1758 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  • Burstein, D. et al. Detecting and adjusting for hidden biases due to phenotype misclassification in genome-wide association studies. Preprint at medRxiv https://doi.org/10.1101/2023.01.17.23284670 (2023).

  • Fawns-Ritchie, C. & Deary, I. J. Reliability and validity of the UK Biobank cognitive tests. PLoS ONE 15, e0231627 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jangmo, A. et al. Attention-deficit/hyperactivity disorder, school performance, and effect of medication. J. Am. Acad. Child Adolesc. Psychiatry 58, 423–432 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Sedgwick, J. A. University students with attention deficit hyperactivity disorder (ADHD): a literature review. Ir. J. Psychol. Med. 35, 221–235 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Kandler, C. et al. The nature of creativity: the roles of genetic factors, personality traits, cognitive abilities, and environmental sources. J. Pers. Soc. Psychol. 111, 230–249 (2016).

    Article  PubMed  Google Scholar 

  • Krueger, R. F. Phenotypic, genetic, and nonshared environmental parallels in the structure of personality: a view from the Multidimensional Personality Questionnaire. J. Pers. Soc. Psychol. 79, 1057–1067 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Judge, T. A., Rodell, J. B., Klinger, R. L., Simon, L. S. & Crawford, E. R. Hierarchical representations of the five-factor model of personality in predicting job performance: integrating three organizing frameworks with two theoretical perspectives. J. Appl. Psychol. 98, 875–925 (2013).

    Article  PubMed  Google Scholar 

  • Oh, I.-S., Wang, G. & Mount, M. K. Validity of observer ratings of the five-factor model of personality traits: a meta-analysis. J. Appl. Psychol. 96, 762–773 (2011).

    Article  PubMed  Google Scholar 

  • Andreasen, N. C. Creativity and mental illness: prevalence rates in writers and their first-degree relatives. Am. J. Psychiatry 144, 1288–1292 (1987).

    Article  CAS  PubMed  Google Scholar 

  • Sedgwick-Müller, J. A. et al. University students with attention deficit hyperactivity disorder (ADHD): a consensus statement from the UK Adult ADHD Network (UKAAN). BMC Psychiatry 22, 292 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  • Fabiano, G. A. et al. Special education for children with ADHD: services received and a comparison to children with ADHD in general education. Sch. Ment. Health 14, 818–830 (2022).

    Article  Google Scholar 

  • Fabiano, G. A. & Pyle, K. Best practices in school mental health for attention-deficit/hyperactivity disorder: a framework for intervention. Sch. Ment. Health 11, 72–91 (2018).

    Article  Google Scholar 

  • Rivera, L. A. & Tilcsik, A. Not in my schoolyard: disability discrimination in educational access. Am. Sociol. Rev. 88, 284–321 (2023).

    Article  Google Scholar 

  • Eisenberg, D. & Schneider, H. Perceptions of academic skills of children diagnosed with ADHD. J. Atten. Disord. 10, 390–397 (2007).

    Article  PubMed  Google Scholar 

  • Walker, J. S., Coleman, D., Lee, J., Squire, P. N. & Friesen, B. J. Children’s stigmatization of childhood depression and ADHD: magnitude and demographic variation in a national sample. J. Am. Acad. Child Adolesc. Psychiatry 47, 912–920 (2008).

    Article  PubMed  Google Scholar 

  • Efron, D., Wijaya, M., Hazell, P. & Sciberras, E. Peer victimization in children with ADHD: a community-based longitudinal study. J. Atten. Disord. 25, 291–299 (2021).

    Article  PubMed  Google Scholar 

  • Tyrrell, J. et al. Genetic predictors of participation in optional components of UK Biobank. Nat. Commun. 12, 886 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pirastu, N. et al. Genetic analyses identify widespread sex-differential participation bias. Nat. Genet. 53, 663–671 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolfram, T. (Not just) intelligence stratifies the occupational hierarchy: ranking 360 professions by IQ and non-cognitive traits. Intelligence 98, 101755 (2023).

    Article  Google Scholar 

  • Young, A. I., Benonisdottir, S., Przeworski, M. & Kong, A. Deconstructing the sources of genotype–phenotype associations in humans. Science 365, 1396–1400 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morris, T. T., Davies, N. M., Hemani, G. & Smith, G. D. Population phenomena inflate genetic associations of complex social traits. Sci. Adv. 6, eaay0328 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howe, L. J. et al. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects. Nat. Genet. 54, 581–592 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okbay, A. et al. Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals. Nat. Genet. 54, 437–449 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young, A. I. et al. Mendelian imputation of parental genotypes improves estimates of direct genetic effects. Nat. Genet. 54, 897–905 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young, A. I. et al. Relatedness disequilibrium regression estimates heritability without environmental bias. Nat. Genet. 50, 1304–1310 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kong, A. et al. The nature of nurture: effects of parental genotypes. Science 359, 424–428 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Selzam, S. et al. Comparing within- and between-family polygenic score prediction. Am. J. Hum. Genet. 105, 351–363 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajagopal, V. M. et al. Genome-wide association study of school grades identifies genetic overlap between language ability, psychopathology and creativity. Sci. Rep. 13, 429 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaziano, J. M. et al. Million Veteran Program: a mega-biobank to study genetic influences on health and disease. J. Clin. Epidemiol. 70, 214–223 (2016).

    Article  PubMed  Google Scholar 

  • Wu, P. et al. Mapping ICD-10 and ICD-10-CM codes to phecodes: workflow development and initial evaluation. JMIR Med. Inform. 7, e14325 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Whitbourne, S. B. et al. Million Veteran Program’s response to COVID-19: survey development and preliminary findings. PLoS ONE 17, e0266381 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kind, A. J. H. & Buckingham, W. R. Making neighborhood-disadvantage metrics accessible: the neighborhood atlas. N. Engl. J. Med. 378, 2456–2458 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • 2020 Area Deprivation Index v.3.2 https://www.neighborhoodatlas.medicine.wisc.edu/ (University of Wisconsin School of Medicine and Public Health, accessed 8 March 2023).

  • Marees, A. T. et al. A tutorial on conducting genome-wide association studies: quality control and statistical analysis. Int. J. Methods Psychiatr. Res. 27, e1608 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • 1000 Genomes Project Consortiumet al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Article  Google Scholar 

  • Klarin, D. et al. Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease. Nat. Genet. 51, 1574–1579 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loh, P.-R., Palamara, P. F. & Price, A. L. Fast and accurate long-range phasing in a UK Biobank cohort. Nat. Genet. 48, 811–816 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G. R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gelernter, J. et al. Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans. Nat. Neurosci. 22, 1394–1401 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manichaikul, A. et al. Robust relationship inference in genome-wide association studies. Bioinformatics 26, 2867–2873 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Fang, H. et al. Harmonizing genetic ancestry and self-identified race/ethnicity in genome-wide association studies. Am. J. Hum. Genet. 105, 763–772 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ge, T., Chen, C.-Y., Ni, Y., Feng, Y.-C. A. & Smoller, J. W. Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nat. Commun. 10, 1776 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, s13742-015-0047-8 (2015).

    Article  Google Scholar 

  • R Core Team. R: a language and environment for statistical computing. https://www.R-project.org/ (R Foundation for Statistical Computing, 2023).

  • Hoffman, G. E. & Schadt, E. E. variancePartition: interpreting drivers of variation in complex gene expression studies. BMC Bioinform. 17, 483 (2016).

    Article  Google Scholar 

  • Nakagawa, S., Johnson, P. C. D. & Schielzeth, H. The coefficient of determination R2 and intra-class correlation coefficient from generalized linear mixed-effects models revisited and expanded. J. R. Soc. Interface 14, 20170213 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  • Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  • Davis, K. A. S. et al. Mental health in UK Biobank—development, implementation and results from an online questionnaire completed by 157 366 participants: a reanalysis. BJPsych Open 6, e18 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  • Noble, M., Wright, G., Smith, G. & Dibben, C. Measuring multiple deprivation at the small-area level. Environ. Plan. A 38, 169–185 (2006).

    Article  Google Scholar 

  • Wain, L. V. et al. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir. Med. 3, 769–781 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  • Galinsky, K. J. et al. Fast principal-component analysis reveals convergent evolution of ADH1B in Europe and East Asia. Am. J. Hum. Genet. 98, 456–472 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar