Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals

Abstract

Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with a study comparing 1247 individuals with mean IQ ~170 to 8185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

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Acknowledgements

We gratefully acknowledge the contribution of all of the researchers and participants involved in the collection and analysis of the data included. This study includes data from Sniekers et al. (2017), which made use of the UK Biobank resource under application number 16,406 (as previously acknowledged). Analysis in this paper represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Analyses were performed using high performance computing facilities funded with capital equipment grants from the GSTT Charity (TR130505) and Maudsley Charity (980). Analysis from Sniekers et al. (2017) was funded by the Netherlands Organization for Scientific Research (NWO VICI 453-14-005), and carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO:480-05-003), by VU University, Amsterdam, the Netherlands, and by the Dutch Brain Foundation and is hosted by the Dutch National Computing and Networking Services SurfSARA. PRJ is supported by the ‘Stichting Vrienden van Sophia’ (grant nr: 14-27) awarded to DP. Research on the HiQ cohort was supported by a European Research Council Advanced Investigator award (295366) to RP. Collecting DNA from the highest-scoring TIP individuals was supported by an award from the John Templeton Foundation (13575) to RP. JB was supported by the Swiss National Science Foundation. Summary statistics from this analysis have been made available at the NHGRI-EBI GWAS Catalog (http://www.ebi.ac.uk/gwas/).

Author contributions

GB, DP, and PFS conceived the study. JRIC, JB, HAG, PRJ, JS, and NS performed statistical analyses. RP, ABM, SL, GC, and JH acquired data. JRIC and GB wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Danielle Posthuma or Gerome Breen.

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PFS reports the following potentially competing financial interests: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member), and Roche (grant recipient, speaker reimbursement). GB reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. All remaining authors declare that they have no conflict of interest.

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Coleman, J.R.I., Bryois, J., Gaspar, H.A. et al. Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals. Mol Psychiatry 24, 182–197 (2019). https://doi.org/10.1038/s41380-018-0040-6

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