Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum

Andrea Ganna¹, F Kyle Satterstrom², Seyedeh M Zekavat³, Indraniel Das⁴, Mitja I Kurki⁵, Claire Churchhouse², Jessica Alfoldi⁶, Alicia R Martin², Aki S Havulinna⁷, Andrea Byrnes², Wesley K Thompson⁸, Philip R Nielsen⁹, Konrad J Karczewski⁶, Elmo Saarentaus¹⁰, Manuel A Rivas¹¹, Namrata Gupta¹², Olli Pietiläinen¹³, Connor A Emdin¹², Francesco Lescai¹⁴, Jonas Bybjerg-Grauholm¹⁵, Jason Flannick³; GoT2D/T2D-GENES Consortium; Josep M Mercader¹⁶, Miriam Udler¹⁶; SIGMA Consortium Helmsley IBD Exome Sequencing Project; FinMetSeq Consortium; iPSYCH-Broad Consortium; Markku Laakso¹⁷, Veikko Salomaa¹⁸, Christina Hultman¹⁹, Samuli Ripatti²⁰, Eija Hämäläinen¹⁰, Jukka S Moilanen²¹, Jarmo Körkkö²¹, Outi Kuismin²¹, Merete Nordentoft²², David M Hougaard¹⁵, Ole Mors²³, Thomas Werge²⁴, Preben Bo Mortensen²⁵, Daniel MacArthur⁶, Mark J Daly², Patrick F Sullivan²⁶, Adam E Locke⁴, Aarno Palotie²⁷, Anders D Børglum¹⁴, Sekar Kathiresan³, Benjamin M Neale²⁸

Affiliations

¹ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17176, Sweden. Electronic address: aganna@broadinstitute.org.
² Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
⁴ McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
⁵ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland.
⁶ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸ Department of Psychiatry, University of California, San Diego, CA 94143, USA; Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde 4000, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0318, Norway.
⁹ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus 8210, Denmark; Centre for Integrated Register-based Research, Aarhus University, Aarhus 8210, Denmark.
¹⁰ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland.
¹¹ Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
¹² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, University of Harvard, Cambridge, MA 02138, USA.
¹⁴ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus 8210, Denmark; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus 8210, Denmark.
¹⁵ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen 2300, Denmark.
¹⁶ Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio 70211, Finland.
¹⁸ Department of Health, THL-National Institute for Health and Welfare, Helsinki 00271, Finland.
¹⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17176, Sweden.
²⁰ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland; Department of Public Health, University of Helsinki, Helsinki 00014, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
²¹ Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu 90029, Finland.
²² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen 2100, Denmark.
²³ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Psychosis Research Unit, Aarhus University Hospital, Risskov 8240, Denmark.
²⁴ Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde 4000, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark.
²⁵ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus 8210, Denmark; Centre for Integrated Register-based Research, Aarhus University, Aarhus 8210, Denmark; iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus 8210, Denmark.
²⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17176, Sweden; Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA.
²⁷ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland.
²⁸ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: bneale@broadinstitute.org.

PMID: 29861106
PMCID: PMC5992130
DOI: 10.1016/j.ajhg.2018.05.002

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum

Andrea Ganna et al. Am J Hum Genet. 2018.

. 2018 Jun 7;102(6):1204-1211.

doi: 10.1016/j.ajhg.2018.05.002. Epub 2018 May 31.

Authors

Affiliations

¹ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17176, Sweden. Electronic address: aganna@broadinstitute.org.
² Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
⁴ McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
⁵ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland.
⁶ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸ Department of Psychiatry, University of California, San Diego, CA 94143, USA; Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde 4000, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0318, Norway.
⁹ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus 8210, Denmark; Centre for Integrated Register-based Research, Aarhus University, Aarhus 8210, Denmark.
¹⁰ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland.
¹¹ Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
¹² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, University of Harvard, Cambridge, MA 02138, USA.
¹⁴ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus 8210, Denmark; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus 8210, Denmark.
¹⁵ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen 2300, Denmark.
¹⁶ Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio 70211, Finland.
¹⁸ Department of Health, THL-National Institute for Health and Welfare, Helsinki 00271, Finland.
¹⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17176, Sweden.
²⁰ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland; Department of Public Health, University of Helsinki, Helsinki 00014, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
²¹ Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu 90029, Finland.
²² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen 2100, Denmark.
²³ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Psychosis Research Unit, Aarhus University Hospital, Risskov 8240, Denmark.
²⁴ Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde 4000, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark.
²⁵ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark; National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus 8210, Denmark; Centre for Integrated Register-based Research, Aarhus University, Aarhus 8210, Denmark; iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus 8210, Denmark.
²⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17176, Sweden; Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA.
²⁷ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland.
²⁸ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: bneale@broadinstitute.org.

PMID: 29861106
PMCID: PMC5992130
DOI: 10.1016/j.ajhg.2018.05.002

Abstract

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

Keywords: burden analysis; constraint genes; exome sequencing; phewas; rare variants; selection; ultra-rare variants.

PubMed Disclaimer

Figures

**Figure 1**
Variants Frequency Distribution across Different Ethnic Group and Gene Sets (A) Average number of variants per individual in n = 83,439 participants without neurodevelopmental/psychiatric disorders. We report the results separately for each ethnic group. (B) Ratio between PTV/Synonymous for each ethnic group. Abbreviations: Afr, African American; Eas, East Asian; Sas, South Asian; Amr, Latinos; Nfe, non-Finnish European; Asj, Ashkenazi Jewish; Fin, Finnish.

**Figure 2**
Association Analysis for Rare and Ultra-rare Variant Burden (A) Association between PI-PTV burden and continuous traits. We reported the association in standard deviations (SD) to allow for comparison across traits. In parentheses, we reported the number of individual included in the analysis for each trait. The p values are reported only for experiment-wise significant results (p < 2 × 10⁻³), highlighted in red. Bars indicate 95% confidence intervals. All the results are obtained from meta-analyzing study and ethnicity-specific associations. (B) Odds ratio for association between PI-PTV burden and dichotomous traits. In brackets, we reported the number of case and control subjects.

**Figure 3**
Signal Overlap between Rare Variants and GWAS-Derived Gene Sets (A) Association (SKAT test p value) in GWAS-derived gene sets (y axis) between rare PTVs and the phenotypes reported on the x axis. Each gene set is obtained using DEPICT to link SNPs derived from GWAS with p value < 5 × 10⁻⁸ and a candidate gene. In brackets we report the number of genes with at least one PTV in our dataset. p values are reported only for experiment-wise associations (p < 0.0003). (B) Association (SKAT test p value) in GWAS-derived gene sets (y axis) between rare PTVs + damaging missense and the phenotypes reported on the x axis.

See this image and copyright information in PMC

References

1. Amberger J.S., Bocchini C.A., Schiettecatte F., Scott A.F., Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 2015;43:D789–D798. - PMC - PubMed
1. Landrum M.J., Lee J.M., Benson M., Brown G., Chao C., Chitipiralla S., Gu B., Hart J., Hoffman D., Hoover J. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44(D1):D862–D868. - PMC - PubMed
1. Zuk O., Schaffner S.F., Samocha K., Do R., Hechter E., Kathiresan S., Daly M.J., Neale B.M., Sunyaev S.R., Lander E.S. Searching for missing heritability: designing rare variant association studies. Proc. Natl. Acad. Sci. USA. 2014;111:E455–E464. - PMC - PubMed
1. Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., O’Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Exome Aggregation Consortium Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291. - PMC - PubMed
1. Genovese G., Fromer M., Stahl E.A., Ruderfer D.M., Chambert K., Landén M., Moran J.L., Purcell S.M., Sklar P., Sullivan P.F. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 2016;19:1433–1441. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- H1 Connect - Access expert opinions and insights on biomedical research.
- scite Smart Citations

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum

Affiliations

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources