An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
07
12
2019
accepted:
04
09
2020
revised:
02
08
2020
pubmed:
29
10
2020
medline:
19
1
2022
entrez:
28
10
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 33110245
doi: 10.1038/s41431-020-00730-8
pii: 10.1038/s41431-020-00730-8
pmc: PMC7868371
doi:
Substances chimiques
Biomarkers
0
Cytokines
0
SERPINE2 protein, human
0
Serpin E2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
309-324Investigateurs
Aarno Palotie
(A)
Mark Daly
(M)
Howard Jacob
(H)
Athena Matakidou
(A)
Heiko Runz
(H)
Sally John
(S)
Robert Plenge
(R)
Mark McCarthy
(M)
Julie Hunkapiller
(J)
Meg Ehm
(M)
Dawn Waterworth
(D)
Caroline Fox
(C)
Anders Malarstig
(A)
Kathy Klinger
(K)
Kathy Call
(K)
Tomi Mäkelä
(T)
Jaakko Kaprio
(J)
Petri Virolainen
(P)
Kari Pulkki
(K)
Terhi Kilpi
(T)
Markus Perola
(M)
Jukka Partanen
(J)
Anne Pitkäranta
(A)
Riitta Kaarteenaho
(R)
Seppo Vainio
(S)
Kimmo Savinainen
(K)
Veli-Matti Kosma
(VM)
Urho Kujala
(U)
Outi Tuovila
(O)
Minna Hendolin
(M)
Raimo Pakkanen
(R)
Jeff Waring
(J)
Bridget Riley-Gillis
(B)
Athena Matakidou
(A)
Heiko Runz
(H)
Jimmy Liu
(J)
Shameek Biswas
(S)
Julie Hunkapiller
(J)
Dawn Waterworth
(D)
Meg Ehm
(M)
Dorothee Diogo
(D)
Caroline Fox
(C)
Anders Malarstig
(A)
Catherine Marshall
(C)
Xinli Hu
(X)
Kathy Call
(K)
Kathy Klinger
(K)
Matthias Gossel
(M)
Samuli Ripatti
(S)
Johanna Schleutker
(J)
Markus Perola
(M)
Mikko Arvas
(M)
Olli Carpen
(O)
Reetta Hinttala
(R)
Johannes Kettunen
(J)
Reijo Laaksonen
(R)
Arto Mannermaa
(A)
Juha Paloneva
(J)
Urho Kujala
(U)
Outi Tuovila
(O)
Minna Hendolin
(M)
Raimo Pakkanen
(R)
Hilkka Soininen
(H)
Valtteri Julkunen
(V)
Anne Remes
(A)
Reetta Kälviäinen
(R)
Mikko Hiltunen
(M)
Jukka Peltola
(J)
Pentti Tienari
(P)
Juha Rinne
(J)
Adam Ziemann
(A)
Jeffrey Waring
(J)
Sahar Esmaeeli
(S)
Nizar Smaoui
(N)
Anne Lehtonen
(A)
Susan Eaton
(S)
Heiko Runz
(H)
Sanni Lahdenperä
(S)
Shameek Biswas
(S)
John Michon
(J)
Geoff Kerchner
(G)
Julie Hunkapiller
(J)
Natalie Bowers
(N)
Edmond Teng
(E)
John Eicher
(J)
Vinay Mehta
(V)
Padhraig Gormley
(P)
Kari Linden
(K)
Christopher Whelan
(C)
Fanli Xu
(F)
David Pulford
(D)
Martti Färkkilä
(M)
Sampsa Pikkarainen
(S)
Airi Jussila
(A)
Timo Blomster
(T)
Mikko Kiviniemi
(M)
Markku Voutilainen
(M)
Bob Georgantas
(B)
Graham Heap
(G)
Jeffrey Waring
(J)
Nizar Smaoui
(N)
Fedik Rahimov
(F)
Anne Lehtonen
(A)
Keith Usiskin
(K)
Joseph Maranville
(J)
Tim Lu
(T)
Natalie Bowers
(N)
Danny Oh
(D)
John Michon
(J)
Vinay Mehta
(V)
Kirsi Kalpala
(K)
Melissa Miller
(M)
Xinli Hu
(X)
Linda McCarthy
(L)
Kari Eklund
(K)
Antti Palomäki
(A)
Pia Isomäki
(P)
Laura Pirilä
(L)
Oili Kaipiainen-Seppänen
(O)
Johanna Huhtakangas
(J)
Bob Georgantas
(B)
Jeffrey Waring
(J)
Fedik Rahimov
(F)
Apinya Lertratanakul
(A)
Nizar Smaoui
(N)
Anne Lehtonen
(A)
David Close
(D)
Marla Hochfeld
(M)
Natalie Bowers
(N)
John Michon
(J)
Dorothee Diogo
(D)
Vinay Mehta
(V)
Kirsi Kalpala
(K)
Nan Bing
(N)
Xinli Hu
(X)
Jorge Esparza Gordillo
(J)
Nina Mars
(N)
Tarja Laitinen
(T)
Margit Pelkonen
(M)
Paula Kauppi
(P)
Hannu Kankaanranta
(H)
Terttu Harju
(T)
Nizar Smaoui
(N)
David Close
(D)
Steven Greenberg
(S)
Hubert Chen
(H)
Natalie Bowers
(N)
John Michon
(J)
Vinay Mehta
(V)
Jo Betts
(J)
Soumitra Ghosh
(S)
Veikko Salomaa
(V)
Teemu Niiranen
(T)
Markus Juonala
(M)
Kaj Metsärinne
(K)
Mika Kähönen
(M)
Juhani Junttila
(J)
Markku Laakso
(M)
Jussi Pihlajamäki
(J)
Juha Sinisalo
(J)
Marja-Riitta Taskinen
(MR)
Tiinamaija Tuomi
(T)
Jari Laukkanen
(J)
Ben Challis
(B)
Andrew Peterson
(A)
Julie Hunkapiller
(J)
Natalie Bowers
(N)
John Michon
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Dorothee Diogo
(D)
Audrey Chu
(A)
Vinay Mehta
(V)
Jaakko Parkkinen
(J)
Melissa Miller
(M)
Anthony Muslin
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Dawn Waterworth
(D)
Heikki Joensuu
(H)
Tuomo Meretoja
(T)
Olli Carpen
(O)
Lauri Aaltonen
(L)
Annika Auranen
(A)
Peeter Karihtala
(P)
Saila Kauppila
(S)
Päivi Auvinen
(P)
Klaus Elenius
(K)
Relja Popovic
(R)
Jeffrey Waring
(J)
Bridget Riley-Gillis
(B)
Anne Lehtonen
(A)
Athena Matakidou
(A)
Jennifer Schutzman
(J)
Julie Hunkapiller
(J)
Natalie Bowers
(N)
John Michon
(J)
Vinay Mehta
(V)
Andrey Loboda
(A)
Aparna Chhibber
(A)
Heli Lehtonen
(H)
Stefan McDonough
(S)
Marika Crohns
(M)
Diptee Kulkarni
(D)
Kai Kaarniranta
(K)
Joni Turunen
(J)
Terhi Ollila
(T)
Sanna Seitsonen
(S)
Hannu Uusitalo
(H)
Vesa Aaltonen
(V)
Hannele Uusitalo-Järvinen
(H)
Marja Luodonpää
(M)
Nina Hautala
(N)
Heiko Runz
(H)
Erich Strauss
(E)
Natalie Bowers
(N)
Hao Chen
(H)
John Michon
(J)
Anna Podgornaia
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Vinay Mehta
(V)
Dorothee Diogo
(D)
Joshua Hoffman
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Kaisa Tasanen
(K)
Laura Huilaja
(L)
Katariina Hannula-Jouppi
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Teea Salmi
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Sirkku Peltonen
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Leena Koulu
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Ilkka Harvima
(I)
Kirsi Kalpala
(K)
Ying Wu
(Y)
David Choy
(D)
John Michon
(J)
Nizar Smaoui
(N)
Fedik Rahimov
(F)
Anne Lehtonen
(A)
Dawn Waterworth
(D)
Anu Jalanko
(A)
Risto Kajanne
(R)
Ulrike Lyhs
(U)
Mari Kaunisto
(M)
Justin Wade Davis
(JW)
Bridget Riley-Gillis
(B)
Danjuma Quarless
(D)
Slavé Petrovski
(S)
Jimmy Liu
(J)
Chia-Yen Chen
(CY)
Paola Bronson
(P)
Robert Yang
(R)
Joseph Maranville
(J)
Shameek Biswas
(S)
Diana Chang
(D)
Julie Hunkapiller
(J)
Tushar Bhangale
(T)
Natalie Bowers
(N)
Dorothee Diogo
(D)
Emily Holzinger
(E)
Padhraig Gormley
(P)
Xulong Wang
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Xing Chen
(X)
Åsa Hedman
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Kirsi Auro
(K)
Clarence Wang
(C)
Ethan Xu
(E)
Franck Auge
(F)
Clement Chatelain
(C)
Mitja Kurki
(M)
Samuli Ripatti
(S)
Mark Daly
(M)
Juha Karjalainen
(J)
Aki Havulinna
(A)
Anu Jalanko
(A)
Kimmo Palin
(K)
Priit Palta
(P)
Pietro Della Briotta Parolo
(P)
Wei Zhou
(W)
Susanna Lemmelä
(S)
Manuel Rivas
(M)
Jarmo Harju
(J)
Aarno Palotie
(A)
Arto Lehisto
(A)
Andrea Ganna
(A)
Vincent Llorens
(V)
Antti Karlsson
(A)
Kati Kristiansson
(K)
Mikko Arvas
(M)
Kati Hyvärinen
(K)
Jarmo Ritari
(J)
Tiina Wahlfors
(T)
Miika Koskinen
(M)
Olli Carpen
(O)
Johannes Kettunen
(J)
Katri Pylkäs
(K)
Marita Kalaoja
(M)
Minna Karjalainen
(M)
Tuomo Mantere
(T)
Eeva Kangasniemi
(E)
Sami Heikkinen
(S)
Arto Mannermaa
(A)
Eija Laakkonen
(E)
Juha Kononen
(J)
Anu Loukola
(A)
Päivi Laiho
(P)
Tuuli Sistonen
(T)
Essi Kaiharju
(E)
Markku Laukkanen
(M)
Elina Järvensivu
(E)
Sini Lähteenmäki
(S)
Lotta Männikkö
(L)
Regis Wong
(R)
Kati Kristiansson
(K)
Hannele Mattsson
(H)
Susanna Lemmelä
(S)
Tero Hiekkalinna
(T)
Manuel González Jiménez
(M)
Kati Donner
(K)
Priit Palta
(P)
Kalle Pärn
(K)
Javier Nunez-Fontarnau
(J)
Jarmo Harju
(J)
Elina Kilpeläinen
(E)
Timo P Sipilä
(TP)
Georg Brein
(G)
Alexander Dada
(A)
Ghazal Awaisa
(G)
Anastasia Shcherban
(A)
Tuomas Sipilä
(T)
Hannele Laivuori
(H)
Aki Havulinna
(A)
Susanna Lemmelä
(S)
Tuomo Kiiskinen
(T)
Tarja Laitinen
(T)
Harri Siirtola
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Javier Gracia Tabuenca
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Lila Kallio
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Sirpa Soini
(S)
Jukka Partanen
(J)
Kimmo Pitkänen
(K)
Seppo Vainio
(S)
Kimmo Savinainen
(K)
Veli-Matti Kosma
(VM)
Teijo Kuopio
(T)
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