Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes : A Large-Scale Cross-Consortium Mendelian Randomization Study
| Autor: | 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., Williams, Julie, PAGE Consortium, International Stroke Genetics Consortium, Systemic Sclerosis consortium, Treat OA consortium, DIAGRAM Consortium, CARDIoGRAMplusC4D Consortium, ALS consortium, International Parkinson’s Disease Genomics Consortium, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, CKDGen consortium, GERAD1 Consortium, International Consortium for Blood Pressure, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Inflammation Working Group of the CHARGE Consortium |
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| Přispěvatelé: | Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Epidemiology, Markus, Hugh [0000-0002-9794-5996], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Knees Social Sciences Blood Pressure Vascular Medicine Biochemistry PAGE Consortium chemistry.chemical_compound 0302 clinical medicine Sociology Consortia Treat OA consortium GENETIC-VARIANTS Medicine and Health Sciences CARDIoGRAMplusC4D Consortium Medicine ALS consortium SUSCEPTIBILITY LOCUS Musculoskeletal System ALL-CAUSE MORTALITY Schizophrenia Working Group of the Psychiatric Genomics Consortium biology Mental Disorders COMMON VARIANTS BIPOLAR DISORDER Genomics 11 Medical And Health Sciences General Medicine International Parkinson’s Disease Genomics Consortium 3. Good health C-Reactive Protein Immune System Diseases CARDIOVASCULAR-DISEASE International Consortium for Blood Pressure Legs Anatomy Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium Research Article Biotechnology medicine.medical_specialty Genotype Heart Diseases Systemic Sclerosis consortium Renal function DIAGRAM Consortium Polymorphism Single Nucleotide International Stroke Genetics Consortium 03 medical and health sciences Rheumatology Metabolic Diseases General & Internal Medicine Statistical significance Mental Health and Psychiatry Osteoarthritis Mendelian randomization Genetics Genome-Wide Association Studies Journal Article Humans CORONARY-HEART-DISEASE GENOME-WIDE ASSOCIATION Psychiatry Molecular Biology Inflammation Working Group of the CHARGE Consortium Creatinine Mood Disorders business.industry Arthritis Limbs (Anatomy) C-reactive protein Biology and Life Sciences Computational Biology Human Genetics Odds ratio Cell Biology Mendelian Randomization Analysis Genome Analysis GERAD1 Consortium RISK LOCI BODY-MASS INDEX 030104 developmental biology Blood pressure chemistry CKDGen consortium Genetics of Disease C400 Genetics Schizophrenia RC0321 biology.protein business Body mass index 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | PLOS MEDICINE, 13(6):e1001976. PUBLIC LIBRARY SCIENCE Prins, B P, Abbasi, A, Wong, A, Vaez, A, Nolte, I, Franceschini, N, Stuart, P E, Guterriez Achury, J, Mistry, V, Bradfield, J P, Valdes, A M, Bras, J, Shatunov, A, Lu, C, Han, B, Raychaudhuri, S, Bevan, S, Mayes, M D, Tsoi, L C, Evangelou, E, Nair, R P, Grant, S F A, Polychronakos, C, Radstake, T R D, van Heel, D A, Dunstan, M L, Wood, N W, Al-Chalabi, A, Dehghan, A, Hakonarson, H, Markus, H S, Elder, J T, Knight, J, Arking, D E, Spector, T D, Koeleman, B P C, van Duijn, C M, Martin, J, Morris, A P, Weersma, R K, Wijmenga, C, Munroe, P B, Perry, J R B, Pouget, J G, Jamshidi, Y, Snieder, H, 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 ', PL o S Medicine, vol. 13, no. 6, e1001976 . https://doi.org/10.1371/journal.pmed.1001976, https://doi.org/10.1371/journal.pmed.1001976 Prins, B P, Abbasi, A, Wong, A, Vaez, A, Nolte, I, Franceschini, N, Stuart, P E, Guterriez Achury, J, Mistry, V, Bradfield, J P, Valdes, A M, Bras, J, Shatunov, A, Lu, C, Han, B, Raychaudhuri, S, Bevan, S, Mayes, M D, Tsoi, L C, Evangelou, E, Nair, R P, Grant, S F A, Polychronakos, C, Radstake, T R D, van Heel, D A, Dunstan, M L, Wood, N W, Al-Chalabi, A, Dehghan, A, Hakonarson, H, Markus, H S, Elder, J T, Knight, J, Arking, D E, Spector, T D, Koeleman, B P C, van Duijn, C M, Martin, J, Morris, A P, Weersma, R K, Wijmenga, C, Munroe, P B, Perry, J R B, Pouget, J G, Jamshidi, Y, Snieder, H, Alizadeh, B Z & PAGE Consortium 2016, ' Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study ', PL o S Medicine, vol. 13, no. 6, pp. e1001976 . https://doi.org/10.1371/journal.pmed.1001976 PLOS MEDICINE PLoS Medicine PLoS Medicine, 13(6). Public Library of Science PLoS Medicine, Vol 13, Iss 6, p e1001976 (2016) PLoS Medicine (online), 13(6):e1001976. Public Library of Science |
| ISSN: | 1549-1277 1549-1676 |
| DOI: | 10.1371/journal.pmed.1001976 |
| Popis: | 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. Using genetic instruments, Behrooz Z. Alizadeh and colleagues examine the hypothesis that increased CRP levels play a causal role in common somatic and psychiatric conditions. Editors' Summary Background Inflammation is an important part of the human immune response, the network of cells and molecules that protects the body from attack by pathogens (infectious organisms) and from harmful substances and foreign particles (for example, splinters). When human cells are attacked by pathogens or injured by trauma or chemicals, molecules called inflammatory mediators induce fluid leakage from the blood vessels into the damaged tissue and attract “phagocytes” (a type of immune cell) to the site of infection or injury to “eat” the germs and dead or damaged cells. The end result is inflammation, which is characterized by swelling, redness, heat, and pain. The inflammatory response, although unpleasant, limits the damage caused by foreign invaders or chemicals by preventing further contact with body tissues. Sometimes, however, inflammation can be harmful. Persistent dysregulation of the inflammatory response is implicated in numerous somatic disorders (diseases that affect the body, such as cardiovascular disease) and neuropsychiatric disorders (mental disorders attributable to diseases of the nervous system, such as schizophrenia). Why Was This Study Done? Observational studies suggest that increased blood levels of C-reactive protein (CRP, an inflammatory protein) are associated with certain somatic and neuropsychiatric disorders. But observational studies cannot prove that changes in CRP levels actually cause any of these disorders. It could be that the individuals who develop a specific disease and who have a high CRP level also share another unknown characteristic that is actually responsible for disease development (confounding). Alternatively, it could be that the disease itself increases CRP levels (reverse causation). It is important to know whether CRP is causally involved in the development of specific diseases because it might then be possible to prevent or treat these diseases using drugs that control CRP levels. Here, the researchers undertake a Mendelian randomization study to determine whether CRP has a causal relationship with 32 common complex somatic and neuropsychiatric outcomes. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if CRP levels actually cause a specific somatic or neuropsychiatric disease, genetic variants that affect CRP levels should be associated with an altered risk for that disease. What Did the Researchers Do and Find? The researchers used data collected by several consortia involved in large genome-wide association studies (studies that ask whether specific genetic changes across the whole human genome, or blueprint, are associated with specific diseases) to look for associations between 32 somatic and neuropsychiatric outcomes and two genetic risk scores (GRSs) for CRP level. GRSCRP consisted of four single nucleotide polymorphisms (SNPs; a type of genetic variant) in the gene encoding CRP; GRSGWAS consisted of 18 SNPs that were associated with CRP level in a genome-wide association study. The researchers report that a genetically increased CRP level was significantly associated with a reduced risk of schizophrenia (a significant association is one unlikely to have arisen by chance). In addition, they found a nominally significant association (an association that needs to be confirmed) between genetically increased CRP levels and an increased risk of knee osteoarthritis, raised diastolic and systolic blood pressure, and bipolar disorder. Notably, there was no evidence for an effect of genetically increased CRP levels on any of the other 27 outcomes studied. What Do These Findings Mean? These findings suggest that genetically raised levels of CRP are causally associated with protection against schizophrenia, an unexpected finding given other recent studies that suggest that raised CRP levels and brain inflammation predispose individuals to schizophrenia. The findings also provide preliminary evidence that genetically raised levels of CRP may be causally associated with an increased risk of raised blood pressure, knee arthritis, and bipolar disorder. The lack of any association between genetically raised levels of CRP and the other outcomes studied suggests, however, that many previously identified disease-associated rises in CRP levels might be a response to the disease process rather than a cause of these diseases. Like all Mendelian randomization studies, the reliability of these findings depends on the validity of several assumptions made by the researchers and on the ability of the GRSs used in the study to explain variations in CRP level. Importantly, however, these findings suggest that interventions designed to lower CRP level are unlikely to decrease the risk of people developing the majority of common complex somatic and neuropsychiatric outcomes. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001976. Wikipedia has pages on inflammation, C-reactive protein, and Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) The MedlinePlus encyclopedia has a page on C-reactive protein (in English and Spanish) The American Heart Association provides a short article on inflammation and heart disease A UK National Health Service “Behind the Headlines” article explains a recent study that found an association between immune activity in the brain and schizophrenia |
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