Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study.
C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.



We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses.



Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Bram P
BP
Prins
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.|Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Ali
0000-0002-6452-4765
A
Abbasi
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.|Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Anson
0000-0001-7269-9429
A
Wong
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
Ahmad
A
Vaez
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Ilja
I
Nolte
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Nora
N
Franceschini
Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America.
Philip E
0000-0002-9546-6529
PE
Stuart
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
Javier
J
Guterriez Achury
Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.|Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Vanisha
V
Mistry
Center for Applied Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States of America.
Jonathan P
JP
Bradfield
Department of Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom.
Ana M
AM
Valdes
Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom.
Jose
J
Bras
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Aleksey
A
Shatunov
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
Chen
C
Lu
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Buhm
B
Han
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America.|Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
Soumya
S
Raychaudhuri
Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
Steve
S
Bevan
Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
Maureen D
MD
Mayes
Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America.
Lam C
LC
Tsoi
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.|Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
Evangelos
E
Evangelou
Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America.
Rajan P
RP
Nair
Center for Applied Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States of America.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America.
Struan F A
SF
Grant
Endocrine Genetics Research Institute, McGill University Health Center, Montreal, Quebec, Canada.
Constantin
C
Polychronakos
Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
Timothy R D
TR
Radstake
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
David A
DA
van Heel
Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Melanie L
0000-0003-3817-2142
ML
Dunstan
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
Nicholas W
NW
Wood
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.|Complex Disease Genetics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.
Ammar
A
Al-Chalabi
Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
Abbas
A
Dehghan
Center for Applied Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States of America.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America.
Hakon
H
Hakonarson
Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
Hugh S
HS
Markus
Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America.
James T
JT
Elder
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
Jo
J
Knight
McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Dan E
DE
Arking
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Timothy D
TD
Spector
Complex Genetic Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Bobby P C
BP
Koeleman
Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
Cornelia M
CM
van Duijn
Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
Javier
J
Martin
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
Andrew P
AP
Morris
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Rinse K
RK
Weersma
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
Cisca
C
Wijmenga
NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.|Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
Patricia B
PB
Munroe
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
John R B
JR
Perry
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Jennie G
JG
Pouget
Cardiogenetics Lab, Cardiovascular and Cell Sciences Institute, St George's Hospital Medical School, London, United Kingdom.
Yalda
Y
Jamshidi
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Harold
H
Snieder
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Behrooz Z
BZ
Alizadeh
D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism; D055106:Genome-Wide Association Study; D005838:Genotype; D006331:Heart Diseases / Q000235:genetics*; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D057182:Mendelian Randomization Analysis; D001523:Mental Disorders / Q000235:genetics*; D008659:Metabolic Diseases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D002097:C-Reactive Protein