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An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease

Abstract

Multivariate methods are known to increase the statistical power to detect associations in the case of shared genetic basis between phenotypes. They have, however, lacked essential analytic tools to follow-up and understand the biology underlying these associations. We developed a novel computational workflow for multivariate GWAS follow-up analyses, including fine-mapping and identification of the subset of traits driving associations (driver traits). Many follow-up tools require univariate regression coefficients which are lacking from multivariate results. Our method overcomes this problem by using Canonical Correlation Analysis to turn each multivariate association into its optimal univariate Linear Combination Phenotype (LCP). This enables an LCP-GWAS, which in turn generates the statistics required for follow-up analyses. We implemented our method on 12 highly correlated inflammatory biomarkers in a Finnish population-based study. Altogether, we identified 11 associations, four of which (F5, ABO, C1orf140 and PDGFRB) were not detected by biomarker-specific analyses. Fine-mapping identified 19 signals within the 11 loci and driver trait analysis determined the traits contributing to the associations. A phenome-wide association study on the 19 representative variants from the signals in 176,899 individuals from the FinnGen study revealed 53 disease associations (p < 1 × 10–4). Several reported pQTLs in the 11 loci provided orthogonal evidence for the biologically relevant functions of the representative variants. Our novel multivariate analysis workflow provides a powerful addition to standard univariate GWAS analyses by enabling multivariate GWAS follow-up and thus promoting the advancement of powerful multivariate methods in genomics.

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Fig. 1: Study workflow.
Fig. 2: Power comparison between multivariate and univariate methods.
Fig. 3: Manhattan plot of the multivariate GWAS results on 12 inflammatory biomarkers.

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Acknowledgements

We would like to thank Lea Urpa for proofreading, and Sari Kivikko, Huei-Yi Shen, and Ulla Tuomainen for management assistance. We would like to thank all participants of the FINRISK, FinnGen and UKBB studies for their generous participation. The FINRISK data used for the research were obtained from THL Biobank. This research has been conducted using the UK Biobank Resource with application number 22627. This work was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics [Grant No 312062 to SR, 312076 to MP, 312074 to AP, 312075 to MD]; Academy of Finland [Grant No 285380 to SR, 288509 to MP, 128650 to AP]; the Finnish Foundation for Cardiovascular Research [to SR, VS, and AP]; the Sigrid Jusélius Foundation [to SR, MP, and AP]; University of Helsinki HiLIFE Fellow grants 2017-2020 [to SR and MP]; Foundation and the Horizon 2020 Research and Innovation Programme [grant number 667301 (COSYN) to AP]; the Doctoral Programme in Population Health, University of Helsinki [to JJP and SER]; and The Finnish Medical Foundation [to JJP]. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and nine industry partners (AbbVie, AstraZeneca, Biogen, Celgene, Genentech, GSK, MSD, Pfizer and Sanofi). Following biobanks are acknowledged for collecting the FinnGen project samples: Auria Biobank (https://www.auria.fi/biopankki/en), THL Biobank (https://thl.fi/fi/web/thl-biopankki), Helsinki Biobank (https://www.terveyskyla.fi/helsinginbiopankki/en), Northern Finland Biobank Borealis (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki), Finnish Clinical Biobank Tampere (https://www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (https://ita-suomenbiopankki.fi/), Central Finland Biobank (https://www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (https://www.bloodservice.fi/Research%20Projects/biobanking). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

FinnGen

Steering Committee: Aarno Palotie13,14, Mark Daly13,14

Pharmaceutical companies: Howard Jacob15, Athena Matakidou16, Heiko Runz17, Sally John17, Robert Plenge18, Mark McCarthy19, Julie Hunkapiller19, Meg Ehm20, Dawn Waterworth20, Caroline Fox21, Anders Malarstig22, Kathy Klinger23, Kathy Call23

University of Helsinki & Biobanks: Tomi Mäkelä24, Jaakko Kaprio13, Petri Virolainen25, Kari Pulkki25, Terhi Kilpi26, Markus Perola26, Jukka Partanen27, Anne Pitkäranta28, Riitta Kaarteenaho29, Seppo Vainio29, Kimmo Savinainen30, Veli-Matti Kosma31, Urho Kujala32

Other Experts/ Non-Voting Members: Outi Tuovila33, Minna Hendolin33, Raimo Pakkanen33

Scientific Committee Pharmaceutical companies: Jeff Waring15, Bridget Riley-Gillis15, Athena Matakidou16, Heiko Runz17, Jimmy Liu17, Shameek Biswas18, Julie Hunkapiller19, Dawn Waterworth20, Meg Ehm20, Dorothee Diogo21, Caroline Fox21, Anders Malarstig22, Catherine Marshall22, Xinli Hu22, Kathy Call23, Kathy Klinger23, Matthias Gossel23

University of Helsinki & Biobanks: Samuli Ripatti13,14, Johanna Schleutker25, Markus Perola26, Mikko Arvas27, Olli Carpen28, Reetta Hinttala29, Johannes Kettunen29, Reijo Laaksonen30, Arto Mannermaa31, Juha Paloneva32, Urho Kujala32

Other Experts/ Non-Voting Members: Outi Tuovila33, Minna Hendolin33, Raimo Pakkanen33

Clinical Groups Neurology Group: Hilkka Soininen34, Valtteri Julkunen34, Anne Remes35, Reetta Kälviäinen34, Mikko Hiltunen34, Jukka Peltola36, Pentti Tienari28, Juha Rinne37, Adam Ziemann15, Jeffrey Waring15, Sahar Esmaeeli15, Nizar Smaoui15, Anne Lehtonen15, Susan Eaton17, Heiko Runz17, Sanni Lahdenperä17, Shameek Biswas18, John Michon19, Geoff Kerchner19, Julie Hunkapiller19, Natalie Bowers19, Edmond Teng19, John Eicher21, Vinay Mehta21, Padhraig Gormley21, Kari Linden22, Christopher Whelan22, Fanli Xu20, David Pulford20

Gastroenterology Group: Martti Färkkilä28, Sampsa Pikkarainen28, Airi Jussila36, Timo Blomster35, Mikko Kiviniemi34, Markku Voutilainen37, Bob Georgantas15, Graham Heap15, Jeffrey Waring15, Nizar Smaoui15, Fedik Rahimov15, Anne Lehtonen15, Keith Usiskin18, Joseph Maranville18, Tim Lu19, Natalie Bowers19, Danny Oh19, John Michon19, Vinay Mehta21, Kirsi Kalpala22, Melissa Miller22, Xinli Hu22, Linda McCarthy20

Rheumatology Group: Kari Eklund28, Antti Palomäki37, Pia Isomäki36, Laura Pirilä37, Oili Kaipiainen-Seppänen34, Johanna Huhtakangas35, Bob Georgantas15, Jeffrey Waring15, Fedik Rahimov15, Apinya Lertratanakul15, Nizar Smaoui15, Anne Lehtonen15, David Close16, Marla Hochfeld18, Natalie Bowers19, John Michon19, Dorothee Diogo21, Vinay Mehta21, Kirsi Kalpala22, Nan Bing22, Xinli Hu22, Jorge Esparza Gordillo20, Nina Mars13

Pulmonology Group: Tarja Laitinen36, Margit Pelkonen34, Paula Kauppi28, Hannu Kankaanranta36, Terttu Harju35, Nizar Smaoui15, David Close16, Steven Greenberg18, Hubert Chen19, Natalie Bowers19, John Michon19, Vinay Mehta21, Jo Betts20, Soumitra Ghosh20

Cardiometabolic Diseases Group: Veikko Salomaa38, Teemu Niiranen38, Markus Juonala37, Kaj Metsärinne37, Mika Kähönen36, Juhani Junttila35, Markku Laakso34, Jussi Pihlajamäki34, Juha Sinisalo28, Marja-Riitta Taskinen28, Tiinamaija Tuomi28, Jari Laukkanen39, Ben Challis16, Andrew Peterson19, Julie Hunkapiller19, Natalie Bowers19, John Michon19, Dorothee Diogo21, Audrey Chu21, Vinay Mehta21, Jaakko Parkkinen22, Melissa Miller22, Anthony Muslin23, Dawn Waterworth20

Oncology Group: Heikki Joensuu28, Tuomo Meretoja28, Olli Carpen28, Lauri Aaltonen28, Annika Auranen36, Peeter Karihtala35, Saila Kauppila35, Päivi Auvinen34, Klaus Elenius37, Relja Popovic15, Jeffrey Waring15, Bridget Riley-Gillis15, Anne Lehtonen15, Athena Matakidou16, Jennifer Schutzman19, Julie Hunkapiller19, Natalie Bowers19, John Michon19, Vinay Mehta21, Andrey Loboda21, Aparna Chhibber21, Heli Lehtonen22, Stefan McDonough22, Marika Crohns23, Diptee Kulkarni20

Opthalmology Group: Kai Kaarniranta34, Joni Turunen28, Terhi Ollila28, Sanna Seitsonen28, Hannu Uusitalo36, Vesa Aaltonen37, Hannele Uusitalo-Järvinen36, Marja Luodonpää35, Nina Hautala35, Heiko Runz17, Erich Strauss19, Natalie Bowers19, Hao Chen19, John Michon19, Anna Podgornaia21, Vinay Mehta21, Dorothee Diogo21, Joshua Hoffman20

Dermatology Group: Kaisa Tasanen35, Laura Huilaja35, Katariina Hannula-Jouppi28, Teea Salmi36, Sirkku Peltonen37, Leena Koulu37, Ilkka Harvima34, Kirsi Kalpala22, Ying Wu22, David Choy19, John Michon19, Nizar Smaoui15, Fedik Rahimov15, Anne Lehtonen15, Dawn Waterworth20

FinnGen Teams: Administration Team Administration Team: Anu Jalanko13, Risto Kajanne13, Ulrike Lyhs13

Communication: Mari Kaunisto13

Analysis Team: Justin Wade Davis15, Bridget Riley-Gillis15, Danjuma Quarless15, Slavé Petrovski16, Jimmy Liu17, Chia-Yen Chen17, Paola Bronson17, Robert Yang18, Joseph Maranville18, Shameek Biswas18, Diana Chang19, Julie Hunkapiller19, Tushar Bhangale19, Natalie Bowers19, Dorothee Diogo21, Emily Holzinger21, Padhraig Gormley21, Xulong Wang21, Xing Chen22, Åsa Hedman22, Kirsi Auro20, Clarence Wang23, Ethan Xu23, Franck Auge23, Clement Chatelain23, Mitja Kurki13,14, Samuli Ripatti13,14, Mark Daly13,14, Juha Karjalainen13,14, Aki Havulinna13, Anu Jalanko13, Kimmo Palin40, Priit Palta13, Pietro Della Briotta Parolo13, Wei Zhou13, Susanna Lemmelä13, Manuel Rivas41, Jarmo Harju13, Aarno Palotie13,14, Arto Lehisto13, Andrea Ganna13, Vincent Llorens13, Antti Karlsson25, Kati Kristiansson26, Mikko Arvas27, Kati Hyvärinen27, Jarmo Ritari27, Tiina Wahlfors27, Miika Koskinen28, Olli Carpen28, Johannes Kettunen29, Katri Pylkäs29, Marita Kalaoja29, Minna Karjalainen29, Tuomo Mantere29, Eeva Kangasniemi30, Sami Heikkinen31, Arto Mannermaa31, Eija Laakkonen32, Juha Kononen32

Sample Collection Coordination: Anu Loukola28

Sample Logistics: Päivi Laiho26, Tuuli Sistonen26, Essi Kaiharju26, Markku Laukkanen26, Elina Järvensivu26, Sini Lähteenmäki26, Lotta Männikkö26, Regis Wong26

Registry Data Operations: Kati Kristiansson26, Hannele Mattsson26, Susanna Lemmelä13, Tero Hiekkalinna26, Manuel González Jiménez26GenotypingKati Donner13

Sequencing Informatics: Priit Palta13, Kalle Pärn13, Javier Nunez-Fontarnau13

Data Management and IT Infrastructure: Jarmo Harju13, Elina Kilpeläinen13, Timo P. Sipilä13, Georg Brein13, Alexander Dada13, Ghazal Awaisa13, Anastasia Shcherban13, Tuomas Sipilä13

Clinical Endpoint Development: Hannele Laivuori13, Aki Havulinna13, Susanna Lemmelä13, Tuomo Kiiskinen13Trajectory TeamTarja Laitinen36, Harri Siirtola42, Javier Gracia Tabuenca42

Biobank Directors: Lila Kallio43, Sirpa Soini44, Jukka Partanen45, Kimmo Pitkänen46, Seppo Vainio47, Kimmo Savinainen48, Veli-Matti Kosma49, Teijo Kuopio50

Data sharing and declaration

Full summary statistics of the multivariate GWAS on the 12 inflammatory biomarkers are available via the NHGRI-EBI GWAS Catalog, accession number GCST90000584. The FinnGen data may be accessed through Finnish Biobanks’ FinnBB portal (www.finbb.fi) and THL Biobank data through THL Biobank (https://thl.fi/en/web/thl-biobank).

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Correspondence to Samuli Ripatti or Jukka Koskela.

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VS has received honoraria from Novo Nordisk and Sanofi for consultations and has ongoing research collaboration with Bayer AG (all unrelated to this study). All other authors have no conflict of interest.

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Members of FinnGen are listed below Acknowledgements.

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Ruotsalainen, S.E., Partanen, J.J., Cichonska, A. et al. An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease. Eur J Hum Genet 29, 309–324 (2021). https://doi.org/10.1038/s41431-020-00730-8

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