Inflammation Working Group of the CHARGE Consortium
Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study
Inflammation Working Group of the CHARGE Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; International Consortium for Blood Pressure; GERAD1 Consortium; CKDGen consortium; Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium; International Parkinson?s Disease Genomics Consortium; ALS consortium; CARDIoGRAMplusC4D Consortium; DIAGRAM Consortium; Treat OA consortium; Systemic Sclerosis consortium; International Stroke Genetics Consortium; PAGE Consortium; Prins, Bram. P.; Abbasi, Ali; Wong, Anson; Vaez, Ahmad; Nolte, Ilja; Franceschini, Nora; Stuart, Philip E.; Guterriez Achury, Javier; Mistry, Vanisha; Bradfield, Jonathan P.; Valdes, Ana M.; Bras, Jose; Shatunov, Aleksey; Lu, Chen; Han, Buhm; Raychaudhuri, Soumya; Bevan, Steve; Mayes, Maureen D.; Tsoi, Lam C.; Evangelou, Evangelos; Nair, Rajan P.; Grant, Struan F.A.; Polychronakos, Constantin; Radstake, Timothy R.D.; van Heel, David A.; Dunstan, Melanie L.; Wood, Nicholas W.; Al-C...
Authors
Schizophrenia Working Group of the Psychiatric Genomics Consortium
International Consortium for Blood Pressure
GERAD1 Consortium
CKDGen consortium
Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium
International Parkinson�s Disease Genomics Consortium
ALS consortium
CARDIoGRAMplusC4D Consortium
DIAGRAM Consortium
Treat OA consortium
Systemic Sclerosis consortium
International Stroke Genetics Consortium
PAGE Consortium
Bram. P. Prins
Ali Abbasi
Anson Wong
Ahmad Vaez
Ilja Nolte
Nora Franceschini
Philip E. Stuart
Javier Guterriez Achury
Vanisha Mistry
Jonathan P. Bradfield
Professor ANA VALDES Ana.Valdes@nottingham.ac.uk
Professor of Molecular & Genetic Epidemiology
Jose Bras
Aleksey Shatunov
Chen Lu
Buhm Han
Soumya Raychaudhuri
Steve Bevan
Maureen D. Mayes
Lam C. Tsoi
Evangelos Evangelou
Rajan P. Nair
Struan F.A. Grant
Constantin Polychronakos
Timothy R.D. Radstake
David A. van Heel
Melanie L. Dunstan
Nicholas W. Wood
Ammar Al-Chalabi
Abbas Dehghan
Hakon Hakonarson
Hugh S. Markus
James T. Elder
Jo Knight
Dan E. Arking
Timothy D. Spector
Bobby P.C. Koeleman
Cornelia M. van Duijn
Javier Martin
Andrew P. Morris
Rinse K. Weersma
Cisca Wijmenga
Patricia B. Munroe
John R.B. Perry
Jennie G. Pouget
Yalda Jamshidi
Harold Snieder
Behrooz Z. Alizadeh
Contributors
Phillipa J. Hay
Editor
Abstract
Background
C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.
Methods and Findings
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.
Conclusions
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.
Citation
Inflammation Working Group of the CHARGE Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, International Consortium for Blood Pressure, GERAD1 Consortium, CKDGen consortium, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, …Alizadeh, B. Z. (2016). Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study. PLoS Medicine, 13(6), e1001976. https://doi.org/10.1371/journal.pmed.1001976
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 3, 2016 |
Online Publication Date | Jun 21, 2016 |
Publication Date | Jun 21, 2016 |
Deposit Date | Sep 5, 2018 |
Publicly Available Date | Jun 22, 2016 |
Journal | PLOS Medicine |
Print ISSN | 1549-1277 |
Electronic ISSN | 1549-1676 |
Publisher | Public Library of Science |
Peer Reviewed | Peer Reviewed |
Volume | 13 |
Issue | 6 |
Pages | e1001976 |
DOI | https://doi.org/10.1371/journal.pmed.1001976 |
Public URL | https://nottingham-repository.worktribe.com/output/1123037 |
Publisher URL | https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001976 |
PMID | 27327646 |
Contract Date | Jan 10, 2019 |
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