Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders
(1)
,
(2, 3)
,
(2, 4)
,
(5)
,
(1, 6)
,
(2)
,
(7)
,
(2)
,
(8)
,
(9)
,
(10)
,
(11)
,
(12)
,
(13)
,
,
(14)
,
,
(15)
,
(16)
,
,
,
,
,
,
(17)
,
,
(18)
,
,
,
(19)
,
(20)
,
,
,
,
,
(21)
,
(22)
,
,
,
,
,
(6)
,
(23)
,
(24)
,
(25)
,
(26)
,
(27)
,
,
,
(28)
,
,
,
(29)
,
,
,
(30)
,
,
(31)
,
,
(32)
,
,
,
,
(33)
,
(34)
,
,
,
,
(35)
,
,
(36)
,
,
,
(37)
,
(38)
,
(39)
,
,
,
(40)
,
(41)
,
(42)
,
,
,
(43)
,
(27)
,
,
,
,
(44)
,
,
(45)
,
,
(46)
,
,
,
,
(47)
,
(47)
,
,
,
,
,
,
,
,
,
(48)
,
(49)
,
(50)
,
(51)
,
(52)
,
(53)
,
,
(47)
,
,
,
,
(54)
,
,
,
(55)
,
(47)
,
,
(56)
,
,
,
(57)
,
(58)
,
(16)
,
(47)
,
(59)
,
(60)
,
(61)
,
(62)
,
,
(63)
,
(56)
,
(64)
,
,
(65)
,
,
,
,
,
,
,
,
(66)
,
,
(67)
,
,
(68)
,
(69)
,
,
(70)
,
,
(47)
,
(71)
,
,
(72)
,
(73)
,
,
,
,
(74)
,
,
(75)
,
(7)
,
(72)
,
(76)
,
(77)
,
,
(26)
,
,
(78)
,
(47)
,
,
(79)
,
(56)
,
(80)
,
(81)
,
,
(39)
,
,
,
,
(82)
,
,
,
(83)
,
(52)
,
(84)
,
(85)
,
(86)
,
,
,
,
(8)
,
(87)
,
(10)
,
(88)
,
(82)
,
(89)
,
(1)
,
(90)
,
,
(91)
,
(53)
,
,
(92)
,
(93)
,
(94)
,
(95)
,
(96)
,
(97)
,
(18)
,
(98)
,
(93)
,
(99)
,
,
(100)
,
(101)
,
(102)
,
,
,
,
,
(26)
,
,
(78)
,
,
,
,
(103)
,
(104)
,
(105)
,
(10)
,
(53)
,
,
,
,
,
(106)
,
(107)
,
(108)
,
,
,
,
(109)
,
(44)
,
,
,
,
(110)
,
(111)
,
(112)
,
(5)
,
(113)
,
(114)
,
(115)
,
(116)
,
(117)
,
(50)
,
,
(118)
,
,
(119)
,
,
(8)
,
,
,
,
,
,
,
(120)
,
,
,
,
(39)
,
(121)
,
(122)
,
(12)
,
(123)
,
,
,
(124)
,
(125)
,
,
,
,
(1)
,
,
(93)
,
,
(117)
,
,
,
,
,
(126)
,
(127)
,
,
(61)
,
(128)
,
,
(6)
,
(129)
,
,
(130)
,
(131)
,
(88)
,
(132)
,
,
(133)
,
(47)
,
,
(45)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
Ying Wu
- Function : Author
- PersonId : 766282
- ORCID : 0000-0002-7919-1107
Gu Zhu
- Function : Author
Carlo Sidore
- Function : Author
Massimo Mangino
- Function : Author
- PersonId : 887705
Maria Sabater-Lleal
- Function : Author
John Kemp
- Function : Author
Tim Kacprowski
- Function : Author
Niek Verweij
- Function : Author
Albert Smith
- Function : Author
Carola Marzi
- Function : Author
Kurt Lohman
- Function : Author
Marcus Kleber
- Function : Author
- PersonId : 800150
- ORCID : 0000-0003-0663-7275
Mahmudul Huq
- Function : Author
Efthymia Vlachopoulou
- Function : Author
Leo-Pekka Lyytikäinen
- Function : Author
Christopher Oldmeadow
- Function : Author
Bjarke Feenstra
- Function : Author
Marzyeh Amini
- Function : Author
Jari Lahti
- Function : Author
- PersonId : 775392
- ORCID : 0000-0002-4310-5297
Katharina Schraut
- Function : Author
Jian’an Luan
- Function : Author
Tom Bak
- Function : Author
Fabiola del Greco M.
- Function : Author
Elisabeth Thiering
- Function : Author
Riccardo Marioni
- Function : Author
Evelin Mihailov
- Function : Author
Ayse Bilge Ozel
- Function : Author
Maria Nethander
- Function : Author
Stella Aslibekyan
- Function : Author
Wei Ang
- Function : Author
Ilaria Gandin
- Function : Author
Charles Kooperberg
- Function : Author
Edith Hofer
- Function : Author
Kumar Rajan
- Function : Author
Wouter den Hollander
- Function : Author
Harmen H.M. Draisma
- Function : Author
Hongyan Huang
- Function : Author
Simone Wahl
- Function : Author
Frank Geller
- Function : Author
Peter Joshi
- Function : Author
Benjamin Lehne
- Function : Author
Diego Vozzi
- Function : Author
Marie Verbanck
- Function : Author
- PersonId : 1181220
- IdHAL : marie-verbanck
- ORCID : 0000-0002-1669-572X
Ginevra Biino
- Function : Author
- PersonId : 910145
Yasaman Saba
- Function : Author
Jeff O’connell
- Function : Author
Franco Giulianini
- Function : Author
Patrik K.E. Magnusson
- Function : Author
- PersonId : 800151
- ORCID : 0000-0002-7315-7899
Christie Ballantyne
- Function : Author
Fernando Rivadineira
- Function : Author
Rico Rueedi
- Function : Author
Maristella Steri
- Function : Author
Karl-Heinz Herzig
- Function : Author
David Stott
- Function : Author
Cristina Menni
- Function : Author
Mattias Frånberg
- Function : Author
Beate St. Pourcain
- Function : Author
Peter Kraft
- Function : Author
- PersonId : 765918
- ORCID : 0000-0002-4472-8103
Annette Peters
- Function : Author
- PersonId : 764072
- ORCID : 0000-0001-6645-0985
Graciela Delgado
- Function : Author
Vera Grossmann
- Function : Author
Juha Sinisalo
- Function : Author
Ilkka Seppälä
- Function : Author
Elizabeth Holliday
- Function : Author
Matthijs Moed
- Function : Author
Jingzhong Ding
- Function : Author
Michele Sale
- Function : Author
Yii-Der Chen
- Function : Author
Nicole Soranzo
- Function : Author
- PersonId : 887707
Carla M.T. Tiesler
- Function : Author
Dan Mellström
- Function : Author
Anders Larsson
- Function : Author
- PersonId : 767245
- ORCID : 0000-0003-3161-0402
Yunmei Wang
- Function : Author
William Scott
- Function : Author
Matthias Lorentzon
- Function : Author
John Beilby
- Function : Author
Kathleen Ryan
- Function : Author
Craig Pennell
- Function : Author
Dragana Vuckovic
- Function : Author
Maria Pina Concas
- Function : Author
Carlos Mendes de Leon
- Function : Author
Lavinia Paternoster
- Function : Author
A.W. Musk
- Function : Author
Pamela A.F. Madden
- Function : Author
Mika Kähönen
- Function : Author
- PersonId : 762620
- ORCID : 0000-0002-4510-7341
Magdalena Zoledziewska
- Function : Author
Ville Karhunen
- Function : Author
Stephen Kritchevsky
- Function : Author
Naveed Sattar
- Function : Author
- PersonId : 762622
- ORCID : 0000-0002-1604-2593
Genevieve Lachance
- Function : Author
Eero Kajantie
- Function : Author
- PersonId : 775395
- ORCID : 0000-0001-7081-8391
Rossella Sorice
- Function : Author
- PersonId : 910144
Giovanni Gambaro
- Function : Author
Marie Standl
- Function : Author
- PersonId : 791411
- ORCID : 0000-0002-5345-2049
Cecilia Lindgren
- Function : Author
- PersonId : 919307
Magnus Karlsson
- Function : Author
- PersonId : 796933
- ORCID : 0000-0001-6098-138X
Lars Lind
- Function : Author
- PersonId : 773565
- ORCID : 0000-0003-2335-8542
Jun Li
- Function : Author
- PersonId : 755190
- ORCID : 0000-0002-0043-3506
Trevor Mori
- Function : Author
Eco J.C.N. de Geus
- Function : Author
Andrew Heath
- Function : Author
Juha Auvinen
- Function : Author
Brendan Buckley
- Function : Author
Mark Mcevoy
- Function : Author
Marian Beekman
- Function : Author
Cristina Bombieri
- Function : Author
Francesco Cucca
- Function : Author
Tim Spector
- Function : Author
Michael Boyle
- Function : Author
Diane Becker
- Function : Author
Bradford Worrall
- Function : Author
Greg Gibson
- Function : Author
Ronald Krauss
- Function : Author
Gianluigi Zaza
- Function : Author
Albertine Oldehinkel
- Function : Author
Lyle Palmer
- Function : Author
Sarah Murray
- Function : Author
Reedik Mägi
- Function : Author
Liesbeth Vandenput
- Function : Author
Karl Desch
- Function : Author
Jaspal Kooner
- Function : Author
Caroline Hayward
- Function : Author
- PersonId : 910155
Donna Arnett
- Function : Author
Lawrence Beilin
- Function : Author
Antonietta Robino
- Function : Author
Mario Pirastu
- Function : Author
- PersonId : 910156
Tine Jess
- Function : Author
Ruth J.F. Loos
- Function : Author
Denis Evans
- Function : Author
Sophie Visvikis-Siest
- Function : Author
- PersonId : 740132
- IdHAL : sofia-siest
- ORCID : 0000-0001-8104-8425
- IdRef : 101311532
Marianne Rots
- Function : Author
Bruce H.R. Wolffenbuttel
- Function : Author
Emelia Benjamin
- Function : Author
Abbas Dehghan
- Function : Author
Tarunveer Singh Ahluwalia
- Function : Author
James Meigs
- Function : Author
Russell Tracy
- Function : Author
Behrooz Alizadeh
- Function : Author
Josh Bis
- Function : Author
Nathan Pankratz
- Function : Author
Myron Gross
- Function : Author
Alex Rainer
- Function : Author
Urmo Vaso
- Function : Author
Lude Franke
- Function : Author
Yalda Jamshidi
- Function : Author
- PersonId : 800152
- ORCID : 0000-0003-0151-6482
Sophie Siest
- Function : Author
- PersonId : 740132
- IdHAL : sofia-siest
- ORCID : 0000-0001-8104-8425
- IdRef : 101311532
Ali Abbasi
- Function : Author
Mohammadreza Abdollahi
- Function : Author
Ursula Schick
- Function : Author
Aldi Kraja
- Function : Author
Yi-Hsiang Hsu
- Function : Author
Daniel Tylee
- Function : Author
Alyson Zwicker
- Function : Author
Alanna Morrison
- Function : Author
Cavin Ward-Caviness
- Function : Author
Ken Rice
- Function : Author
Kari Matti Makela
- Function : Author
Tim Frayling
- Function : Author
Abstract
C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
Copyright © 2018 American Society of Human Genetics. All rights reserved.