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Reconciling S-LDSC and LDAK functional enrichment estimates

Nature Genetics volume 51, pages 1202–1204 (2019)Cite this article

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To the Editor — Recent work has highlighted the importance of accounting for linkage disequilibrium (LD)-dependent genetic architectures in analyses of heritability1,2,3,4,5. Two models incorporating LD-dependent architectures have been proposed for analyses of functional enrichment: the baseline-LD model4 used by stratified LD-score regression4,6 (S-LDSC) and the LDAK model1,3. Although both models include LD-dependent effects, they produce very different estimates of functional enrichment (for example, 9.35x ± 0.80 in ref. 4 and 1.34x ± 0.26 in ref. 3 for conserved regions), thus leading to different interpretations of the functional architecture of complex traits. To reconcile these findings, we performed a comprehensive set of formal model comparisons and empirical analyses. Each of these analyses supports the higher functional enrichment estimates of S-LDSC with the baseline-LD model; each paragraph below is detailed in a corresponding section of the Supplementary Note (and detailed analyses can be found in Supplementary Tables 1–10 and Supplementary Figs. 1–23).

We defined six heritability models, including the infinitesimal model that ref. 3 called the ‘GCTA model’7; the baseline-LD model4, combining functional annotations6 with LD-dependent and minor allele frequency (MAF)-dependent architectures; and the LDAK model3, combining LD-dependent and MAF-dependent architectures. Notably, the baseline-LD and LDAK models use very different LD-dependent architectures. For comparison purposes, we also defined the ‘α-model’1, comprising only the MAF-dependent part of the LDAK model; the ‘Gazal-LD model’, comprising only the LD-dependent and MAF-dependent parts of the baseline-LD model (analogous to the LDAK model); and the ‘baseline-LD + LDAK’ model, which flexibly combines baseline-LD and LDAK model annotations.

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Fig. 1: Likelihood comparison of different models of per-SNP heritability.
Fig. 2: Comparison of functional enrichment estimates in analyses of UK Biobank traits.

Data availability

Baseline-LD model version 1.1 can be found at https://data.broadinstitute.org/alkesgroup/LDSCORE/1000G_Phase3_baselineLD_v1.1_ldscores.tgz. UK Biobank association statistics, computed with BOLT-LMM v2.3, are available at http://data.broadinstitute.org/alkesgroup/UKBB/.

Code availability

LDSC software is available at https://github.com/bulik/ldsc. LDAK version 5 is available at http://dougspeed.com/downloads/.

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Acknowledgements

We are grateful to P.-R. Loh for assistance with UK Biobank data and to L. O’Connor, D. Speed and D. Balding for helpful discussions. This research was conducted by using the UK Biobank Resource under Application 16549. A.L.P. is funded by NIH grants U01 HG009379, R01 MH101244 and R01 MH107649. S.G. is funded by NIH K99 HG010160-01. H.K.F. is funded by Eric and Wendy Schmidt and NIH DP5-OD024582. Computational analyses were performed on the Orchestra High-Performance Compute Cluster at Harvard Medical School.

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Author notes

  1. These authors jointly supervised this work: Hilary K. Finucane, Alkes L. Price.

Authors and Affiliations

  1. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Steven Gazal & Alkes L. Price

  2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Steven Gazal, Carla Marquez-Luna, Hilary K. Finucane & Alkes L. Price

  3. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Carla Marquez-Luna & Alkes L. Price

Authors
  1. Steven Gazal
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  2. Carla Marquez-Luna
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  3. Hilary K. Finucane
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  4. Alkes L. Price
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Contributions

S.G., H.K.F. and A.L.P. designed experiments. S.G. performed experiments. S.G., C.M.L. and H.K.F. analyzed data. S.G., H.K.F. and A.L.P., with assistance from C.M.L., wrote the manuscript.

Corresponding authors

Correspondence to Steven Gazal, Hilary K. Finucane or Alkes L. Price.

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The authors declare no competing interests.

Supplementary information

Supplementary Information

Supplementary Notes, Supplementary Figs. 1–23 and Supplementary Tables 1 and 5

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Supplementary Tables

Supplementary Tables 2–4 and 6–10

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Gazal, S., Marquez-Luna, C., Finucane, H.K. et al. Reconciling S-LDSC and LDAK functional enrichment estimates. Nat Genet 51, 1202–1204 (2019). https://doi.org/10.1038/s41588-019-0464-1

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