Analysis with the exome array identifies multiple new independent variants in lipid loci

Stavroula Kanoni¹, Nicholas G D Masca^{2

3}, Kathleen E Stirrups^{1

4}, Tibor V Varga^{5

6

7}, Helen R Warren^{8

9}, Robert A Scott¹⁰, Lorraine Southam^{4

11}, Weihua Zhang^{12

13}, Hanieh Yaghootkar¹⁴, Martina Müller-Nurasyid^{15

16

17

18}, Alexessander Couto Alves¹⁹, Rona J Strawbridge²⁰, Lazaros Lataniotis¹, Nikman An Hashim²¹, Céline Besse²², Anne Boland²², Peter S Braund^{2

3}, John M Connell²³, Anna Dominiczak²⁴, Aliki-Eleni Farmaki²⁵, Stephen Franks²⁶, Harald Grallert^{27

28

29}, Jan-Håkan Jansson³⁰, Maria Karaleftheri³¹, Sirkka Keinänen-Kiukaanniemi³², Angela Matchan⁴, Dorota Pasko¹⁴, Annette Peters^{18

28}, Neil Poulter³³, Nigel W Rayner^{4

11

34}, Frida Renström^{7

35}, Olov Rolandsson³⁶, Maria Sabater-Lleal²⁰, Bengt Sennblad^{20

37}, Peter Sever³³, Denis Shields³⁸, Angela Silveira²⁰, Alice V Stanton³⁹, Konstantin Strauch^{16

17}, Maciej Tomaszewski^{2

3}, Emmanouil Tsafantakis⁴⁰, Melanie Waldenberger^{27

28}, Alexandra I F Blakemore^{21

41}, George Dedoussis²⁵, Stefan A Escher⁷, Jaspal S Kooner^{13

42

43}, Mark I McCarthy^{11

34

44}, Colin N A Palmer²³; Wellcome Trust Case Control Consortium; Anders Hamsten²⁰, Mark J Caulfield^{1

9}, Timothy M Frayling¹⁴, Martin D Tobin⁴⁵, Marjo-Riitta Jarvelin^{19

32

46

47

48}, Eleftheria Zeggini⁴, Christian Gieger^{27

28

29}, John C Chambers^{12

13

42}, Nick J Wareham⁸, Patricia B Munroe^{1

9}, Paul W Franks^{7

49

50}, Nilesh J Samani^{51

3}, Panos Deloukas^{52

53}

Affiliations

¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
² Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK.
³ NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK.
⁴ Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
⁵ The Broad Institute of MIT and Harvard, Boston, MA 02142, USA.
⁶ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
⁸ Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁹ NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁰ Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
¹¹ Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
¹² Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹³ Ealing Hospital NHS Trust, Middlesex, UK.
¹⁴ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
¹⁵ Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
¹⁶ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁷ Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
¹⁸ DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
¹⁹ Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
²⁰ Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
²¹ Section of Investigative Medicine, Imperial College London, London, UK.
²² CEA, Institut de Génomique, Centre National de Génotypage, Evry, France.
²³ Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
²⁴ Division of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Western Infirmary, Glasgow, UK.
²⁵ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University Athens, Athens, Greece.
²⁶ Department of Surgery and Cancer, Imperial College London, Institute of Reproductive and Developmental Biology, London, UK.
²⁷ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
²⁸ Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ German Center for Diabetes Research, Neuherberg, Germany.
³⁰ Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, Umeå, Sweden.
³¹ Echinos Medical Centre, Echinos, Greece.
³² Institute of Health Sciences, University of Oulu, Oulu, Finland.
³³ International Centre for Circulatory Health, Imperial College London, London, UK.
³⁴ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
³⁵ Department of Biobank Research, Umeå University, Umeå, Sweden.
³⁶ Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå University, Umeå, Sweden.
³⁷ Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
³⁸ Complex and Adaptive Systems Laboratory, University College Dublin, Belfield, Dublin, Ireland.
³⁹ Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Stephens Green, Dublin, Ireland.
⁴⁰ Anogia Medical Centre, Anogia, Greece.
⁴¹ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.
⁴² Imperial College Healthcare NHS Trust, London, UK.
⁴³ National Heart and Lung Institute, Imperial College London, London, UK.
⁴⁴ Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.
⁴⁵ Department of Health Sciences, University of Leicester, Leicester, UK.
⁴⁶ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁴⁷ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁴⁸ Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
⁴⁹ Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
⁵⁰ Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.
⁵¹ Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK p.deloukas@qmul.ac.uk.
⁵² William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK p.deloukas@qmul.ac.uk.
⁵³ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

PMID: 27466198
PMCID: PMC5291227
DOI: 10.1093/hmg/ddw227

Analysis with the exome array identifies multiple new independent variants in lipid loci

Stavroula Kanoni et al. Hum Mol Genet. 2016.

. 2016 Sep 15;25(18):4094-4106.

doi: 10.1093/hmg/ddw227. Epub 2016 Jul 27.

Authors

Affiliations

¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
² Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK.
³ NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK.
⁴ Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
⁵ The Broad Institute of MIT and Harvard, Boston, MA 02142, USA.
⁶ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
⁸ Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁹ NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁰ Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
¹¹ Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
¹² Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹³ Ealing Hospital NHS Trust, Middlesex, UK.
¹⁴ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
¹⁵ Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
¹⁶ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁷ Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
¹⁸ DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
¹⁹ Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
²⁰ Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
²¹ Section of Investigative Medicine, Imperial College London, London, UK.
²² CEA, Institut de Génomique, Centre National de Génotypage, Evry, France.
²³ Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
²⁴ Division of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Western Infirmary, Glasgow, UK.
²⁵ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University Athens, Athens, Greece.
²⁶ Department of Surgery and Cancer, Imperial College London, Institute of Reproductive and Developmental Biology, London, UK.
²⁷ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
²⁸ Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ German Center for Diabetes Research, Neuherberg, Germany.
³⁰ Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, Umeå, Sweden.
³¹ Echinos Medical Centre, Echinos, Greece.
³² Institute of Health Sciences, University of Oulu, Oulu, Finland.
³³ International Centre for Circulatory Health, Imperial College London, London, UK.
³⁴ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
³⁵ Department of Biobank Research, Umeå University, Umeå, Sweden.
³⁶ Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå University, Umeå, Sweden.
³⁷ Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
³⁸ Complex and Adaptive Systems Laboratory, University College Dublin, Belfield, Dublin, Ireland.
³⁹ Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Stephens Green, Dublin, Ireland.
⁴⁰ Anogia Medical Centre, Anogia, Greece.
⁴¹ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.
⁴² Imperial College Healthcare NHS Trust, London, UK.
⁴³ National Heart and Lung Institute, Imperial College London, London, UK.
⁴⁴ Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.
⁴⁵ Department of Health Sciences, University of Leicester, Leicester, UK.
⁴⁶ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁴⁷ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁴⁸ Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
⁴⁹ Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
⁵⁰ Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.
⁵¹ Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK p.deloukas@qmul.ac.uk.
⁵² William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK p.deloukas@qmul.ac.uk.
⁵³ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

PMID: 27466198
PMCID: PMC5291227
DOI: 10.1093/hmg/ddw227

Abstract

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.

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Figures

**Figure 1.**
Flow diagram of the study.

**Figure 2.**
Comparison of results between conditional and joint analyses. Note that these figures do not include the lead SNP in each region (i.e. round > 0 means that variants from the conditional analysis are shown only), as the conditional analyses do not produce adjusted estimates of their effects in contrary to the joint analyses.

See this image and copyright information in PMC

References

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Analysis with the exome array identifies multiple new independent variants in lipid loci

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Analysis with the exome array identifies multiple new independent variants in lipid loci

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