Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

doi:10.1038/ncomms11122

. 2016 Mar 23:7:11122.

doi: 10.1038/ncomms11122.

Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Johannes Kettunen^{1

2

3

4}, Ayşe Demirkan^{5

6}, Peter Würtz¹, Harmen H M Draisma^{7

8

9}, Toomas Haller¹⁰, Rajesh Rawal^{11

12}, Anika Vaarhorst¹³, Antti J Kangas¹, Leo-Pekka Lyytikäinen¹⁴, Matti Pirinen¹⁵, René Pool^{7

8}, Antti-Pekka Sarin^{2

15}, Pasi Soininen^{1

3}, Taru Tukiainen^{16

17}, Qin Wang^{1

3}, Mika Tiainen^{1

3}, Tuulia Tynkkynen^{1

3}, Najaf Amin⁶, Tanja Zeller^{18

19}, Marian Beekman¹³, Joris Deelen¹³, Ko Willems van Dijk^{5

20}, Tõnu Esko¹⁰, Jouke-Jan Hottenga^{7

8}, Elisabeth M van Leeuwen⁶, Terho Lehtimäki¹⁴, Evelin Mihailov¹⁰, Richard J Rose^{21

22}, Anton J M de Craen²³, Christian Gieger^{11

12}, Mika Kähönen²⁴, Markus Perola^{2

10

15}, Stefan Blankenberg^{18

19}, Markku J Savolainen^{4

25}, Aswin Verhoeven²⁶, Jorma Viikari²⁷, Gonneke Willemsen^{7

8}, Dorret I Boomsma^{7

8}, Cornelia M van Duijn⁶, Johan Eriksson^{2

28

29}, Antti Jula², Marjo-Riitta Järvelin^{4

30

31

32}, Jaakko Kaprio^{15

21

33}, Andres Metspalu¹⁰, Olli Raitakari^{34

35}, Veikko Salomaa², P Eline Slagboom¹³, Melanie Waldenberger^{11

12}, Samuli Ripatti^{2

15

21

36}, Mika Ala-Korpela^{1

3

4

37

38

39}

Affiliations

¹ Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.
² National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.
³ NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, Kuopio 70210, Finland.
⁴ Biocenter Oulu, University of Oulu, PO Box 5000, FI-90014 Oulu, Finland.
⁵ Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
⁶ Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
⁷ Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Room 2B-29, 1081 BT Amsterdam, The Netherlands.
⁸ EMGO Institute for Health and Care Research, Van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
⁹ Neuroscience Campus Amsterdam, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands.
¹⁰ Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
¹¹ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
¹² Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
¹³ Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
¹⁴ Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere University, Kalevantie 4, Tampere 33014, Finland.
¹⁵ Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum 2, Tukholmankatu 8, Helsinki 00290, Finland.
¹⁶ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
¹⁷ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 0330, Boston, Massachusetts 02115, USA.
¹⁸ German Center for Cardiovascular Research (DZHK e.V.), Partner Site Hamburg/Lübeck/Kiel, Martinistraße 52, 20246 Hamburg, Germany.
¹⁹ University Heart Center Hamburg, Clinic of general and interventional Cardiology, Martinistraße 52, 20246 Hamburg, Germany.
²⁰ Department of Endocrinology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
²¹ Department of Public Health, Hjelt Institute, University of Helsinki, PO Box 41 Mannerheimintie 172, Helsinki 00014, Finland.
²² Department of Psychological and Brain Sciences, Indiana University, 1101 E 10th Street, Bloomington, Indiana 47405, USA.
²³ Department of Geriatrics and Gerontology, Leiden University Medical Center, Postzone C7-Q, PO Box 9600, 2300RC Leiden, The Netherlands.
²⁴ Department of Clinical Physiology, University of Tampere and Tampere, University Hospital, PO Box 2000, FIN-33521 Tampere, Finland.
²⁵ Medical Research Center, Internal Medicine, Oulu University Hospital, University of Oulu, Aapistie 5A, Oulu FI-90220, Finland.
²⁶ Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
²⁷ Department of Medicine, University of Turku and Turku University Hospital, PB 52, 20521 Turku, Finland.
²⁸ Department of General Practice and Primary Health Care, University of Helsinki, PL 20, Tukholmankatu 8B, Helsinki 00029, Finland.
²⁹ Folkhälsan Research Centre, Helsingfors Universitet, PB 63, Helsinki 00014, Finland.
³⁰ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK.
³¹ Center for Life Course and Systems Epidemiology, Faculty of Medicine, University of Oulu, PL 5000, 90014 Oulu, Finland.
³² Unit of Primary Care, Oulu University Hospital, P.O. Box 20, OYS, Oulu 90029, Finland.
³³ Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, PO Box 30 (Mannerheimintie 166), Helsinki 00300, Finland.
³⁴ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 4-8, Turku 20521, Finland.
³⁵ Department of Clinical Physiology, Turku University Hospital, Kiinamyllynkatu 4-8, Turku 20521, Finland.
³⁶ Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
³⁷ Oulu University Hospital, Kajaanintie 50, Oulu 90220, Finland.
³⁸ Computational Medicine, School of Social and Community Medicine, University of Bristol, Senate House, Tyndall Avenue, Bristol, Bristol BS8 1TH, UK.
³⁹ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, Bristol BS8 1TH, UK.

PMID: 27005778
PMCID: PMC4814583
DOI: 10.1038/ncomms11122

Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Johannes Kettunen et al. Nat Commun. 2016.

. 2016 Mar 23:7:11122.

doi: 10.1038/ncomms11122.

Authors

Affiliations

¹ Computational Medicine, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 Oulu, Finland.
² National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland.
³ NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1C, Kuopio 70210, Finland.
⁴ Biocenter Oulu, University of Oulu, PO Box 5000, FI-90014 Oulu, Finland.
⁵ Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
⁶ Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
⁷ Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Room 2B-29, 1081 BT Amsterdam, The Netherlands.
⁸ EMGO Institute for Health and Care Research, Van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
⁹ Neuroscience Campus Amsterdam, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands.
¹⁰ Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
¹¹ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
¹² Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
¹³ Department of Molecular Epidemiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
¹⁴ Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere University, Kalevantie 4, Tampere 33014, Finland.
¹⁵ Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum 2, Tukholmankatu 8, Helsinki 00290, Finland.
¹⁶ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
¹⁷ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 0330, Boston, Massachusetts 02115, USA.
¹⁸ German Center for Cardiovascular Research (DZHK e.V.), Partner Site Hamburg/Lübeck/Kiel, Martinistraße 52, 20246 Hamburg, Germany.
¹⁹ University Heart Center Hamburg, Clinic of general and interventional Cardiology, Martinistraße 52, 20246 Hamburg, Germany.
²⁰ Department of Endocrinology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
²¹ Department of Public Health, Hjelt Institute, University of Helsinki, PO Box 41 Mannerheimintie 172, Helsinki 00014, Finland.
²² Department of Psychological and Brain Sciences, Indiana University, 1101 E 10th Street, Bloomington, Indiana 47405, USA.
²³ Department of Geriatrics and Gerontology, Leiden University Medical Center, Postzone C7-Q, PO Box 9600, 2300RC Leiden, The Netherlands.
²⁴ Department of Clinical Physiology, University of Tampere and Tampere, University Hospital, PO Box 2000, FIN-33521 Tampere, Finland.
²⁵ Medical Research Center, Internal Medicine, Oulu University Hospital, University of Oulu, Aapistie 5A, Oulu FI-90220, Finland.
²⁶ Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
²⁷ Department of Medicine, University of Turku and Turku University Hospital, PB 52, 20521 Turku, Finland.
²⁸ Department of General Practice and Primary Health Care, University of Helsinki, PL 20, Tukholmankatu 8B, Helsinki 00029, Finland.
²⁹ Folkhälsan Research Centre, Helsingfors Universitet, PB 63, Helsinki 00014, Finland.
³⁰ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London SW7 2AZ, UK.
³¹ Center for Life Course and Systems Epidemiology, Faculty of Medicine, University of Oulu, PL 5000, 90014 Oulu, Finland.
³² Unit of Primary Care, Oulu University Hospital, P.O. Box 20, OYS, Oulu 90029, Finland.
³³ Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, PO Box 30 (Mannerheimintie 166), Helsinki 00300, Finland.
³⁴ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 4-8, Turku 20521, Finland.
³⁵ Department of Clinical Physiology, Turku University Hospital, Kiinamyllynkatu 4-8, Turku 20521, Finland.
³⁶ Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
³⁷ Oulu University Hospital, Kajaanintie 50, Oulu 90220, Finland.
³⁸ Computational Medicine, School of Social and Community Medicine, University of Bristol, Senate House, Tyndall Avenue, Bristol, Bristol BS8 1TH, UK.
³⁹ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, Bristol BS8 1TH, UK.

PMID: 27005778
PMCID: PMC4814583
DOI: 10.1038/ncomms11122

Abstract

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.

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Conflict of interest statement

S.B. has received honoraria from Abbott Diagnostics, SIEMENS, Thermo Fisher and Roche Diagnostics and is a consultant for Thermo Fisher. The sponsor played no role in the design or conduct of this study; in the management, analysis or interpretation of the data; or in the preparation, review or approval of the manuscript or in the decision to submit the manuscript for publication. P.W., A.J.K., P.S. and M.A.-K. are shareholders of Brainshake Ltd. (), a company offering NMR-based metabolite profiling. Jo.K., P.W., A.J.K., P.S., Q.W., M.T. and Tu.T. report employment and consulting for Brainshake Ltd. The remaining authors declare no competing financial interests.

Figures

**Figure 1. A genome-wide association study for circulating metabolites.**
Study was conducted to elucidate the genetic variation of systemic metabolism and to discover new metabolic associations in established loci. We also revealed an intriguing novel relation between Lp(a) and systemic triglyceride and VLDL metabolism. Thereby, we highlighted the *LPA* locus and generated the best possible Lp(a) genetic risk score (GRS_Lp(a)) that enabled us to clarify causal associations between Lp(a) and systemic triglyceride and lipoprotein metabolism. Further, with the aid of extensive electronic health-care records, we were able to use the GRS_Lp(a) to show that Lp(a) is associated with ischaemic heart disease but not strongly with other morbidities. Put together, these findings suggest safe molecular intervention on *LPA* to reduce individual cardiovascular risk.

**Figure 2. The association pattern of the Lp(a) variant rs10455872 G-allele across all circulating metabolic traits.**
Each bar represents the association with respective metabolic trait, the size of the bar is the linear regression effect estimate, colouring refers to effect direction and significance is indicated with filled circles for P<2.27 × 10⁻⁹ and unfilled circles for P<5 × 10⁻⁸. Metabolite abbreviations and sample sizes are given in Supplementary Table 1, the strongest association was observed for the mean diameter of very-low-density lipoprotein particles (VLDL.D).

**Figure 3. Evaluation of the causative role of the Lp(a) on the circulating metabolic measures via Mendelian randomization.**
Yellow linear regression estimates are observational associations, blue are GRS_Lp(a) estimates and red are the causal effect estimates. Those metabolic traits are listed for which the associations in the meta-analysis were significant with genome-wide threshold (P<2.3 × 10⁻⁹). Metabolite abbreviations are given in Supplementary Table 1.

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References

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1. Hindorff L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009). - PMC - PubMed
1. Suhre K. & Gieger C. Genetic variation in metabolic phenotypes: study designs and applications. Nat. Rev. Genet. 13, 759–769 (2012). - PubMed
1. Kettunen J. et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nature Genet. 44, 269–276 (2012). - PMC - PubMed
1. Shin S. Y. et al. An atlas of genetic influences on human blood metabolites. Nature Genet. 46, 543–550 (2014). - PMC - PubMed

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[1] Welter D. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014). - PMC - PubMed

[2] Welter D. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014). - PMC - PubMed

[3] Hindorff L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009). - PMC - PubMed

[4] Hindorff L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009). - PMC - PubMed

[5] Suhre K. & Gieger C. Genetic variation in metabolic phenotypes: study designs and applications. Nat. Rev. Genet. 13, 759–769 (2012). - PubMed

[6] Suhre K. & Gieger C. Genetic variation in metabolic phenotypes: study designs and applications. Nat. Rev. Genet. 13, 759–769 (2012). - PubMed

[7] Kettunen J. et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nature Genet. 44, 269–276 (2012). - PMC - PubMed

[8] Kettunen J. et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nature Genet. 44, 269–276 (2012). - PMC - PubMed

[9] Shin S. Y. et al. An atlas of genetic influences on human blood metabolites. Nature Genet. 46, 543–550 (2014). - PMC - PubMed

[10] Shin S. Y. et al. An atlas of genetic influences on human blood metabolites. Nature Genet. 46, 543–550 (2014). - PMC - PubMed

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Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Affiliations

Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

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Conflict of interest statement

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