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Ultra-rare disruptive and damaging mutations influence educational attainment in the general population


Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants of YOE in the general population.

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Figure 1: Association between number of disruptive, damaging and synonymous URVs in HC genes and YOE.
Figure 2: Association between numbers of disruptive, damaging and synonymous URVs for different gene sets.
Figure 3: Association between each of the normalized scores (polygenic, runs of homozygosity, URVs and pathogenic CNVs) and YOE.


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We thank R. Walters for discussions. A.G. is supported by the Knut and Alice Wallenberg Foundation (2015.0327) and the Swedish Research Council (2016-00250). M.G.N. is supported by the Royal Netherlands Academy of Science Professor Award (PAH/6635) to Dorret I. Boomsma. V.S. was supported by the Finnish Foundation for Cardiovascular Research. This study was supported by grants from the National Human Genome Research Institute (U54 HG003067 and R01 HG006855); the National Institute of Mental Health (1U01MH105666-01 and 1R01MH101244-02); the National Institute of Diabetes and Digestive and Kidney Disease (1U54DK105566-02); the Stanley Center for Psychiatric Research; the Alexander and Margaret Stewart Trust; the National Institutes of Mental Health (R01 MH077139 and RC2 MH089905); the Sylvan C. Herman Foundation; EU H2020 grants 692145, 676550 and 654248; Estonian Research Council Grant IUT20-60, NIASC, EIT–Health; NIH-BMI Grant No. 2R01DK075787-06A1; and by the EU through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012 GENTRANSMED).

Author information

Authors and Affiliations



A.G. and G.G. designed the study, performed the analysis and wrote the manuscript. B.M.N. supervised the project. D.H., A. Byrnes, M.I.K., S.M.Z., C.W.W., M.K., M.G.N., P.N. and R.M. performed the analyses. A. Bloemendal, J.M.B., J.I.G., T.P., C.S. and R.E.H. developed and provided computational tools. D.G. provide data management support. E.B.R., A.M., V.S., J.S., S.M.P., P.S., S.K., M.J.D., S.A.M., P.F.S., A.P., T.E. and C.M.H. collected and provided the data.

Corresponding author

Correspondence to Andrea Ganna.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 First three principal components for each study

Supplementary Figure 2 Association between disruptive, damaging and synonymous URVs and YOE in cases and controls of schizophrenia.

Similar associations are observed in cases and control of schizophrenia. Total individuals included N=14,133.

Supplementary Figure 3 Association between disruptive, damaging and synonymous URVs and YOE after excluding individuals with neurodevelopmental disorders.

Only Swedish non-schizophrenic participants are included in this analysis. Similar associations are observed once individuals with neurodevelopmental disorders are excluded.

Supplementary Figure 4 Association between disruptive and damaging URVs with YOE for different quantiles of brain gene-expression.

Only Swedish participants are included (N=10,651).

Supplementary Figure 5 Association between disruptive, damaging and synonymous URVs and YOE in highly brain-specific HC genes, sparsely brain-specific HC genes and all highly brain-specific genes.

Meta-analysis results (N=14,133).

Supplementary Figure 6 Association between polygenic score and YOE, in individuals carrying 0 or ≥1 URVs or pathogenic CNVs

Only Swedish participants are included (N=10,651).

Supplementary Figure 7 Q-Q plots for the gene-based burden test for association between disruptive and damaging variants and YOE.

Each point is a gene. Results are from meta-analysis across studies (N=14,133). In the upper panels we included only URVs, in the lower panels we included variants with minor allele frequency < 0.05%.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 1104 kb)

Supplementary Methods Checklist

(PDF 397 kb)

Supplementary Table 1

Educational attainment coding for each study (XLSX 10 kb)

Supplementary Table 2

Distribution of YOE by study, year of birth and sex (XLSX 10 kb)

Supplementary Table 3

Number and distribution of URVs by study (XLSX 10 kb)

Supplementary Table 4

Large pathogenic CNVs included in the study and number of carriers (XLSX 13 kb)

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Ganna, A., Genovese, G., Howrigan, D. et al. Ultra-rare disruptive and damaging mutations influence educational attainment in the general population. Nat Neurosci 19, 1563–1565 (2016).

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