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Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits

Author

Listed:
  • Andrew D. Grotzinger

    (University of Texas at Austin)

  • Mijke Rhemtulla

    (University of California, Davis)

  • Ronald Vlaming

    (Vrije Universiteit Amsterdam
    Erasmus University Rotterdam Institute for Behavior and Biology)

  • Stuart J. Ritchie

    (University of Edinburgh
    University of Edinburgh)

  • Travis T. Mallard

    (University of Texas at Austin)

  • W. David Hill

    (University of Edinburgh
    University of Edinburgh)

  • Hill F. Ip

    (Vrije Universiteit University Amsterdam)

  • Riccardo E. Marioni

    (University of Edinburgh
    University of Edinburgh)

  • Andrew M. McIntosh

    (University of Edinburgh
    University of Edinburgh)

  • Ian J. Deary

    (University of Edinburgh
    University of Edinburgh)

  • Philipp D. Koellinger

    (Vrije Universiteit Amsterdam
    Erasmus University Rotterdam Institute for Behavior and Biology)

  • K. Paige Harden

    (University of Texas at Austin
    University of Texas at Austin)

  • Michel G. Nivard

    (Vrije Universiteit University Amsterdam)

  • Elliot M. Tucker-Drob

    (University of Texas at Austin
    University of Texas at Austin)

Abstract

Genetic correlations estimated from genome-wide association studies (GWASs) reveal pervasive pleiotropy across a wide variety of phenotypes. We introduce genomic structural equation modelling (genomic SEM): a multivariate method for analysing the joint genetic architecture of complex traits. Genomic SEM synthesizes genetic correlations and single-nucleotide polymorphism heritabilities inferred from GWAS summary statistics of individual traits from samples with varying and unknown degrees of overlap. Genomic SEM can be used to model multivariate genetic associations among phenotypes, identify variants with effects on general dimensions of cross-trait liability, calculate more predictive polygenic scores and identify loci that cause divergence between traits. We demonstrate several applications of genomic SEM, including a joint analysis of summary statistics from five psychiatric traits. We identify 27 independent single-nucleotide polymorphisms not previously identified in the contributing univariate GWASs. Polygenic scores from genomic SEM consistently outperform those from univariate GWASs. Genomic SEM is flexible and open ended, and allows for continuous innovation in multivariate genetic analysis.

Suggested Citation

  • Andrew D. Grotzinger & Mijke Rhemtulla & Ronald Vlaming & Stuart J. Ritchie & Travis T. Mallard & W. David Hill & Hill F. Ip & Riccardo E. Marioni & Andrew M. McIntosh & Ian J. Deary & Philipp D. Koel, 2019. "Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits," Nature Human Behaviour, Nature, vol. 3(5), pages 513-525, May.
    • Handle: RePEc:nat:nathum:v:3:y:2019:i:5:d:10.1038_s41562-019-0566-x
    DOI: 10.1038/s41562-019-0566-x
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    Cited by:

    1. von Stumm, Sophie & Nancarrow, Allie F., 2024. "New methods, persistent issues, and one solution: Gene-environment interaction studies of childhood cognitive development," Intelligence, Elsevier, vol. 105(C).
    2. Knyspel, Jacob & Plomin, Robert, 2024. "Comparing factor and network models of cognitive abilities using twin data," Intelligence, Elsevier, vol. 104(C).
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    4. Clara Albiñana & Zhihong Zhu & Andrew J. Schork & Andrés Ingason & Hugues Aschard & Isabell Brikell & Cynthia M. Bulik & Liselotte V. Petersen & Esben Agerbo & Jakob Grove & Merete Nordentoft & David , 2023. "Multi-PGS enhances polygenic prediction by combining 937 polygenic scores," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Margherita Malanchini & Andrea G. Allegrini & Michel G. Nivard & Pietro Biroli & Kaili Rimfeld & Rosa Cheesman & Sophie Stumm & Perline A. Demange & Elsje Bergen & Andrew D. Grotzinger & Laurel Raffin, 2024. "Genetic associations between non-cognitive skills and academic achievement over development," Nature Human Behaviour, Nature, vol. 8(10), pages 2034-2046, October.
    6. David Westergaard & Frederik Hytting Jørgensen & Jens Waaben & Alexander Wolfgang Jung & Mette Lademann & Thomas Folkmann Hansen & Jolien Cremers & Sisse Rye Ostrowski & Ole Birger Vesterager Pedersen, 2024. "Uncovering the heritable components of multimorbidities and disease trajectories using a nationwide cohort," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    7. Lucía de Hoyos & Maria T. Barendse & Fenja Schlag & Marjolein M. J. van Donkelaar & Ellen Verhoef & Chin Yang Shapland & Alexander Klassmann & Jan Buitelaar & Brad Verhulst & Simon E. Fisher & Dheeraj, 2024. "Structural models of genome-wide covariance identify multiple common dimensions in autism," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Max Lam & Chia-Yen Chen & W. David Hill & Charley Xia & Ruoyu Tian & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Alexander S. Hatoum & Hailiang Huang & Anil K. Malhotra & Heiko Runz & Tian Ge, 2022. "Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    9. Pietro Demela & Nicola Pirastu & Blagoje Soskic, 2023. "Cross-disorder genetic analysis of immune diseases reveals distinct gene associations that converge on common pathways," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    10. Gianmarco Mignogna & Caitlin E. Carey & Robbee Wedow & Nikolas Baya & Mattia Cordioli & Nicola Pirastu & Rino Bellocco & Kathryn Fiuza Malerbi & Michel G. Nivard & Benjamin M. Neale & Raymond K. Walte, 2023. "Patterns of item nonresponse behaviour to survey questionnaires are systematic and associated with genetic loci," Nature Human Behaviour, Nature, vol. 7(8), pages 1371-1387, August.
    11. Caitlin E. Carey & Rebecca Shafee & Robbee Wedow & Amanda Elliott & Duncan S. Palmer & John Compitello & Masahiro Kanai & Liam Abbott & Patrick Schultz & Konrad J. Karczewski & Samuel C. Bryant & Caro, 2024. "Principled distillation of UK Biobank phenotype data reveals underlying structure in human variation," Nature Human Behaviour, Nature, vol. 8(8), pages 1599-1615, August.
    12. Wang, Chao & Zhan, Jinyan & Wang, Huihui & Yang, Zheng & Chu, Xi & Liu, Wei & Teng, Yanmin & Liu, Huizi & Wang, Yifan, 2022. "Multi-group analysis on the mechanism of residents' low-carbon behaviors in Beijing, China," Technological Forecasting and Social Change, Elsevier, vol. 183(C).
    13. Mingyang Li & Xixi Dang & Yiwei Chen & Zhifan Chen & Xinyi Xu & Zhiyong Zhao & Dan Wu, 2024. "Cognitive processing speed and accuracy are intrinsically different in genetic architecture and brain phenotypes," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    14. Hans Kippersluis & Pietro Biroli & Rita Dias Pereira & Titus J. Galama & Stephanie Hinke & S. Fleur W. Meddens & Dilnoza Muslimova & Eric A. W. Slob & Ronald Vlaming & Cornelius A. Rietveld, 2023. "Overcoming attenuation bias in regressions using polygenic indices," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Jonsdottir, Gudrun A. & Einarsson, Gudmundur & Thorleifsson, Gudmar & Magnusson, Sigurdur H. & Gunnarsson, Arni F. & Frigge, Michael L. & Gisladottir, Rosa S. & Unnsteinsdottir, Unnur & Gunnarsson, Bj, 2021. "Genetic propensities for verbal and spatial ability have opposite effects on body mass index and risk of schizophrenia," Intelligence, Elsevier, vol. 88(C).
    16. Michael G. Levin & Noah L. Tsao & Pankhuri Singhal & Chang Liu & Ha My T. Vy & Ishan Paranjpe & Joshua D. Backman & Tiffany R. Bellomo & William P. Bone & Kiran J. Biddinger & Qin Hui & Ozan Dikilitas, 2022. "Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    17. Procopio, Francesca & Zhou, Quan & Wang, Ziye & Gidziela, Agnieska & Rimfeld, Kaili & Malanchini, Margherita & Plomin, Robert, 2022. "The genetics of specific cognitive abilities," Intelligence, Elsevier, vol. 95(C).
    18. Andrew D. Grotzinger & Javier de la Fuente & Gail Davies & Michel G. Nivard & Elliot M. Tucker-Drob, 2022. "Transcriptome-wide and stratified genomic structural equation modeling identify neurobiological pathways shared across diverse cognitive traits," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    19. Royce E. Clifford & Adam X. Maihofer & Chris Chatzinakos & Jonathan R. I. Coleman & Nikolaos P. Daskalakis & Marianna Gasperi & Kelleigh Hogan & Elizabeth A. Mikita & Murray B. Stein & Catherine Tchea, 2024. "Genetic architecture distinguishes tinnitus from hearing loss," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    20. Mattia Marchi & Anne Alkema & Charley Xia & Chris H. L. Thio & Li-Yu Chen & Winni Schalkwijk & Gian M. Galeazzi & Silvia Ferrari & Luca Pingani & Hyeokmoon Kweon & Sara Evans-Lacko & W. David Hill & M, 2024. "Investigating the impact of poverty on mental illness in the UK Biobank using Mendelian randomization," Nature Human Behaviour, Nature, vol. 8(9), pages 1771-1783, September.

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