Supplementary Figure 1

Histogram showing the proportion of genotyping array–based CNV calls that were also called by exome sequencing in 10,091 samples where CNVs from both platforms existed.

The histogram is stratified by the number of exome sequencing targets in which the array-based CNV overlapped.

Nature Genetics: doi:10.1038/ng.3638

Supplementary Figure 2

Histogram showing the number of CNVs called by exome sequencing and the number that were also called by genotyping arrays in 10,091 samples where CNVs from both platforms existed.

The histogram is stratified by the number of exome sequencing targets in which the CNV overlapped.

Nature Genetics: doi:10.1038/ng.3638

Supplementary Figure 3

Correlation of number of CNVs and average read depth by ExAC cohort.

ExAC cohorts stratified by sample and population (corresponding to colors) with mean read depth on the x axis and mean number of CNVs on the y axis.

Nature Genetics: doi:10.1038/ng.3638

Supplementary Figure 4

Average number of CNVs by population and ExAC cohort.

Mean number of CNVs, stratified by ethnicity on the x axis. Each point corresponds to an ExAC cohort (as denoted by its color), and the size of the point is proportional to the size of the subcohort from a particular ethnicity group.

Nature Genetics: doi:10.1038/ng.3638

Supplementary Figure 5

CNV frequency mediated by the number of pairs of segmental duplications within which a gene occurs.

Number of CNVs for each gene, binned by the number of pairs of segmental duplications between which the gene is found; note that 6+ denotes 6 or more pairs.

Nature Genetics: doi:10.1038/ng.3638

Supplementary Figure 6

Distribution of CNV intolerance scores.

Histogram of the CNV intolerance score for each gene before and after winsorizing the most tolerant end of the distribution.

Nature Genetics: doi:10.1038/ng.3638

Supplementary Figure 7

Correlation of CNV intolerance scores and loss-of-function constraint scores.

The violin plots show that increase in CNV intolerance score tracks with increase in both missense and loss-of-function SNV constraint scores stratified by decile.

Nature Genetics: doi:10.1038/ng.3638

Supplementary Note

Monkol Lek1,2,3,4

, Konrad J Karczewski1,2

, Eric V Minikel1,2,5

, Kaitlin E Samocha1,2,6,5

,

Eric Banks2, Timothy Fennell

2, Anne H O'Donnell- Luria

1,2,7, James S Ware

2,8,9,10,11,

Andrew J Hill1,2,12

, Beryl B Cummings1,2,5

, Taru Tukiainen1,2

, Daniel P Birnbaum2, Jack

A Kosmicki1,2,6,13

, Laramie Duncan1,2,6

, Karol Estrada1,2

, Fengmei Zhao1,2

, James Zou2,

Emma Pierce-Hoffman1,2

, David N Cooper14

, Nicole Deflaux15

, Mark DePristo16

, Ron

Do17,18,19,20

, Jason Flannick2,21

, Menachem Fromer1,6,22,17,18

, Laura Gauthier16

, Jackie

Goldstein1,2,6

, Namrata Gupta2, Daniel Howrigan

1,2,6, Adam Kiezun

16, Mitja I Kurki

2,23,

Ami Levy Moonshine16

, Pradeep Natarajan2,24,25,26

, Lorena Orozco27

, Gina M

Peloso2,25,26

, Ryan Poplin16

, Manuel A Rivas2, Valentin Ruano-Rubio

16, Samuel A Rose

6,

Douglas M Ruderfer22,17,18

, Khalid Shakir16

, Peter D Stenson14

, Christine Stevens2, Brett

P Thomas1,2

, Grace Tiao16

, Maria T Tusie-Luna28

, Ben Weisburd2, Hong-Hee

Won2,24,25,26,29

, Dongmei Yu6,25,23,30

, David M Altshuler2,31

, Diego Ardissino32

, Michael

Boehnke33

, John Danesh34

, Stacey Donnelly2, Roberto Elosua

35, Jose C Florez

2,24,25,

Stacey B Gabriel2, Gad Getz

16,24,36, Stephen J Glatt

37,38,39, Christina M Hultman

40, Sekar

Kathiresan2,24,25,26

, Markku Laakso41

, Steven McCarroll6,8

, Mark I McCarthy42,43,44

,

Dermot McGovern45

, Ruth McPherson46

, Benjamin M Neale1,2,6

, Aarno Palotie47

, Shaun

M Purcell22,17,18

, Danish Saleheen48,49,50

, Jeremiah M Scharf2,6,25,23,30

, Pamela

Sklar22,17,18,51,52

, Patrick F Sullivan53,54

, Jaakko Tuomilehto55

, Ming T Tsuang56

, Hugh C

Watkins57,42

, James G Wilson58

, Mark J Daly1,2,6

, Daniel G MacArthur1,2

1. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

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

3. School of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia

4. Institute for Neuroscience and Muscle Research, Childrens Hospital at Westmead, Sydney, NSW, Australia

5. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA

Nature Genetics: doi:10.1038/ng.3638

6. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

7. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA

8. Department of Genetics, Harvard Medical School, Boston, MA, USA

9. National Heart and Lung Institute, Imperial College London, London, UK

10. NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK

11. MRC Clinical Sciences Centre, Imperial College London, London, UK

12. Genome Sciences, University of Washington, Seattle, WA, USA

13. Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA

14. Institute of Medical Genetics, Cardiff University, Cardiff, UK

15. Google Inc, Mountain View, CA, USA

16. Broad Institute of MIT and Harvard, Cambridge, MA, USA

17. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

18. Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

19. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

20. The Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

21. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

22. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

23. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

24. Harvard Medical School, Boston, MA, USA

25. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA,

Nature Genetics: doi:10.1038/ng.3638

USA

26. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

27. Immunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genomica, Mexico City, Mexico

28. Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico

29. Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea

30. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

31. Vertex Pharmaceuticals, Boston, MA, USA

32. Department of Cardiology, University Hospital, Parma, Italy

33. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA

34. Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK

35. Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute, Barcelona, Spain

36. Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA

37. Psychiatric Genetic Epidemiology & Neurobiology Laboratory, State University of New York,Upstate Medical University, Syracuse, NY, USA

38. Department of Psychiatry and Behavioral Sciences, State University of New York,Upstate Medical University, Syracuse, NY, USA

39. Department of Neuroscience and Physiology, State University of New York,Upstate Medical University, Syracuse, NY, USA

40. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden

41. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

42. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

43. Oxford Centre for Diabetes,Endocrinology and Metabolism, University of Oxford,

Nature Genetics: doi:10.1038/ng.3638

Oxford, UK

44. Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK

45. Inflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

46. Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada

47. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

48. Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

49. Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

50. Center for Non-Communicable Diseases, Karachi, Pakistan

51. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

52. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

53. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

54. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

55. Department of Public Health, University of Helsinki, Helsinki, Finland

56. Department of Psychiatry, University of California, San Diego, CA, USA

57. Radcliffe Department of Medicine, University of Oxford, Oxford, UK

58. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

Nature Genetics: doi:10.1038/ng.3638