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 G...

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Published in:	PLoS medicine 2016-06, Vol.13 (6), p.e1001976-e1001976
Main Authors:	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-Chalabi, Ammar, Dehghan, Abbas, Hakonarson, Hakon, Markus, Hugh S, Elder, James T, Knight, Jo, Arking, Dan E, Spector, Timothy D, Koeleman, Bobby P C, van Duijn, Cornelia M, Martin, Javier, Morris, Andrew P, Weersma, Rinse K, Wijmenga, Cisca, Munroe, Patricia B, Perry, John R B, Pouget, Jennie G, Jamshidi, Yalda, Snieder, Harold, Alizadeh, Behrooz Z
Format:	Article
Language:	eng
Subjects:	Analysis Biology and Life Sciences Bipolar disorder C-reactive protein C-Reactive Protein - genetics C-Reactive Protein - metabolism Genome-Wide Association Study Genotype Health risk assessment Heart Diseases - genetics Humans Immune System Diseases - genetics Investigations Medical research Medicine and Health Sciences Mendelian Randomization Analysis Mental disorders Mental Disorders - genetics Mental illness Metabolic Diseases - genetics Outcome and process assessment (Health Care) Outcome and process assessment (Medical care) Polymorphism, Single Nucleotide Risk factors Social Sciences Studies
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Summary:	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 wit
ISSN:	1549-1676 1549-1277 1549-1676