Publication

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

Prins, B. P., Abbasi, A., Wong, A., Vaez, A., Nolte, I., Franceschini, N., Stuart, P. E., Gutierrez 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, Int Stroke Genetics Consortium, Systemic Sclerosis Consortium, Treat OA Consortium, DIAGRAM Consortium, CARDIoGRAMplusC4d Consortium, ALS Consortium, Int Parkinson Dis Genomics Consort, Autism Spectrum Disorder Working G, CKDGen Consortium, GERAD1 Consortium, Int Consortium Blood Pressure, Schizophrenia Working Grp Psychiat & Inflammation Working Grp CHARGE Co, Jun-2016, In : PLOS MEDICINE. 13, 6, 29 p., e1001976.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Prins, B. P., Abbasi, A., Wong, A., Vaez, A., Nolte, I., Franceschini, N., ... Inflammation Working Grp CHARGE Co (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

Author

Prins, Bram. P. ; Abbasi, Ali ; Wong, Anson ; Vaez, Ahmad ; Nolte, Ilja ; Franceschini, Nora ; Stuart, Philip E. ; Gutierrez 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. ; PAGE Consortium ; Int Stroke Genetics Consortium ; Systemic Sclerosis Consortium ; Treat OA Consortium ; DIAGRAM Consortium ; CARDIoGRAMplusC4d Consortium ; ALS Consortium ; Int Parkinson Dis Genomics Consort ; Autism Spectrum Disorder Working G ; CKDGen Consortium ; GERAD1 Consortium ; Int Consortium Blood Pressure ; Schizophrenia Working Grp Psychiat ; Inflammation Working Grp CHARGE Co. / Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes : A Large-Scale Cross-Consortium Mendelian Randomization Study. In: PLOS MEDICINE. 2016 ; Vol. 13, No. 6.

Harvard

Prins, BP, Abbasi, A, Wong, A, Vaez, A, Nolte, I, Franceschini, N, Stuart, PE, Gutierrez Achury, J, Mistry, V, Bradfield, JP, Valdes, AM, Bras, J, Shatunov, A, Lu, C, Han, B, Raychaudhuri, S, Bevan, S, Mayes, MD, Tsoi, LC, Evangelou, E, Nair, RP, Grant, SFA, Polychronakos, C, Radstake, TRD, van Heel, DA, Dunstan, ML, Wood, NW, Al-Chalabi, A, Dehghan, A, Hakonarson, H, Markus, HS, Elder, JT, Knight, J, Arking, DE, Spector, TD, Koeleman, BPC, van Duijn, CM, Martin, J, Morris, AP, Weersma, RK, Wijmenga, C, Munroe, PB, Perry, JRB, Pouget, JG, Jamshidi, Y, Snieder, H, Alizadeh, BZ, PAGE Consortium, Int Stroke Genetics Consortium, Systemic Sclerosis Consortium, Treat OA Consortium, DIAGRAM Consortium, CARDIoGRAMplusC4d Consortium, ALS Consortium, Int Parkinson Dis Genomics Consort, Autism Spectrum Disorder Working G, CKDGen Consortium, GERAD1 Consortium, Int Consortium Blood Pressure, Schizophrenia Working Grp Psychiat & Inflammation Working Grp CHARGE Co 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, vol. 13, no. 6, e1001976. https://doi.org/10.1371/journal.pmed.1001976

Standard

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes : A Large-Scale Cross-Consortium Mendelian Randomization Study. / Prins, Bram. P.; Abbasi, Ali; Wong, Anson; Vaez, Ahmad; Nolte, Ilja; Franceschini, Nora; Stuart, Philip E.; Gutierrez 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.; PAGE Consortium; Int Stroke Genetics Consortium; Systemic Sclerosis Consortium; Treat OA Consortium; DIAGRAM Consortium; CARDIoGRAMplusC4d Consortium; ALS Consortium; Int Parkinson Dis Genomics Consort; Autism Spectrum Disorder Working G; CKDGen Consortium; GERAD1 Consortium; Int Consortium Blood Pressure; Schizophrenia Working Grp Psychiat; Inflammation Working Grp CHARGE Co.

In: PLOS MEDICINE, Vol. 13, No. 6, e1001976, 06.2016.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Prins BP, Abbasi A, Wong A, Vaez A, Nolte I, Franceschini N et al. 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. 2016 Jun;13(6). e1001976. https://doi.org/10.1371/journal.pmed.1001976


BibTeX

@article{0505ce922e754cb98a85cdccf74053aa,
title = "Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study",
abstract = "BackgroundC-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.Methods and FindingsWe 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 (GRS(CRP)), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRS(GWAS)). 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 GRS(CRP) and GRS(GWAS), respectively. CRP GRS(GWAS) 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 x 10(-6)). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 x 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 x 10(-4)) showed a statistically significant (p <2.45 x 10(-4)) protective effect with an OR of 0.97 (95{\%} CI 0.95-0.99). The CRP GRS(GWAS) 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 x 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 m(2) (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.ConclusionsGenetically 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 GRS(CRP) or GRS(GWAS)-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.",
keywords = "GENOME-WIDE ASSOCIATION, CORONARY-HEART-DISEASE, BODY-MASS INDEX, ALL-CAUSE MORTALITY, CARDIOVASCULAR-DISEASE, COMMON VARIANTS, BIPOLAR DISORDER, GENETIC-VARIANTS, RISK LOCI, SUSCEPTIBILITY LOCUS",
author = "Prins, {Bram. P.} and Ali Abbasi and Anson Wong and Ahmad Vaez and Ilja Nolte and Nora Franceschini and Stuart, {Philip E.} and {Gutierrez Achury}, Javier and Vanisha Mistry and Bradfield, {Jonathan P.} and Valdes, {Ana M.} and Jose Bras and Aleksey Shatunov and Chen Lu and Buhm Han and Soumya Raychaudhuri and Steve Bevan and Mayes, {Maureen D.} and Tsoi, {Lam C.} and Evangelos Evangelou and Nair, {Rajan P.} and Grant, {Struan F. A.} and Constantin Polychronakos and Radstake, {Timothy R. D.} and {van Heel}, {David A.} and Dunstan, {Melanie L.} and Wood, {Nicholas W.} and Ammar Al-Chalabi and Abbas Dehghan and Hakon Hakonarson and Markus, {Hugh S.} and Elder, {James T.} and Jo Knight and Arking, {Dan E.} and Spector, {Timothy D.} and Koeleman, {Bobby P. C.} and {van Duijn}, {Cornelia M.} and Javier Martin and Morris, {Andrew P.} and Weersma, {Rinse K.} and Cisca Wijmenga and Munroe, {Patricia B.} and Perry, {John R. B.} and Pouget, {Jennie G.} and Yalda Jamshidi and Harold Snieder and Alizadeh, {Behrooz Z.} and {PAGE Consortium} and {Int Stroke Genetics Consortium} and {Systemic Sclerosis Consortium} and {Treat OA Consortium} and {DIAGRAM Consortium} and {CARDIoGRAMplusC4d Consortium} and {ALS Consortium} and {Int Parkinson Dis Genomics Consort} and {Autism Spectrum Disorder Working G} and {CKDGen Consortium} and {GERAD1 Consortium} and {Int Consortium Blood Pressure} and {Schizophrenia Working Grp Psychiat} and {Inflammation Working Grp CHARGE Co}",
year = "2016",
month = "6",
doi = "10.1371/journal.pmed.1001976",
language = "English",
volume = "13",
journal = "PLOS MEDICINE",
issn = "1549-1277",
publisher = "PUBLIC LIBRARY SCIENCE",
number = "6",

}

RIS

TY - JOUR

T1 - Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes

T2 - A Large-Scale Cross-Consortium Mendelian Randomization Study

AU - Prins, Bram. P.

AU - Abbasi, Ali

AU - Wong, Anson

AU - Vaez, Ahmad

AU - Nolte, Ilja

AU - Franceschini, Nora

AU - Stuart, Philip E.

AU - Gutierrez Achury, Javier

AU - Mistry, Vanisha

AU - Bradfield, Jonathan P.

AU - Valdes, Ana M.

AU - Bras, Jose

AU - Shatunov, Aleksey

AU - Lu, Chen

AU - Han, Buhm

AU - Raychaudhuri, Soumya

AU - Bevan, Steve

AU - Mayes, Maureen D.

AU - Tsoi, Lam C.

AU - Evangelou, Evangelos

AU - Nair, Rajan P.

AU - Grant, Struan F. A.

AU - Polychronakos, Constantin

AU - Radstake, Timothy R. D.

AU - van Heel, David A.

AU - Dunstan, Melanie L.

AU - Wood, Nicholas W.

AU - Al-Chalabi, Ammar

AU - Dehghan, Abbas

AU - Hakonarson, Hakon

AU - Markus, Hugh S.

AU - Elder, James T.

AU - Knight, Jo

AU - Arking, Dan E.

AU - Spector, Timothy D.

AU - Koeleman, Bobby P. C.

AU - van Duijn, Cornelia M.

AU - Martin, Javier

AU - Morris, Andrew P.

AU - Weersma, Rinse K.

AU - Wijmenga, Cisca

AU - Munroe, Patricia B.

AU - Perry, John R. B.

AU - Pouget, Jennie G.

AU - Jamshidi, Yalda

AU - Snieder, Harold

AU - Alizadeh, Behrooz Z.

AU - PAGE Consortium

AU - Int Stroke Genetics Consortium

AU - Systemic Sclerosis Consortium

AU - Treat OA Consortium

AU - DIAGRAM Consortium

AU - CARDIoGRAMplusC4d Consortium

AU - ALS Consortium

AU - Int Parkinson Dis Genomics Consort

AU - Autism Spectrum Disorder Working G

AU - CKDGen Consortium

AU - GERAD1 Consortium

AU - Int Consortium Blood Pressure

AU - Schizophrenia Working Grp Psychiat

AU - Inflammation Working Grp CHARGE Co

PY - 2016/6

Y1 - 2016/6

N2 - BackgroundC-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.Methods and FindingsWe 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 (GRS(CRP)), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRS(GWAS)). 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 GRS(CRP) and GRS(GWAS), respectively. CRP GRS(GWAS) 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 x 10(-6)). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 x 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 x 10(-4)) showed a statistically significant (p <2.45 x 10(-4)) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRS(GWAS) 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 x 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 m(2) (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.ConclusionsGenetically 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 GRS(CRP) or GRS(GWAS)-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.

AB - BackgroundC-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.Methods and FindingsWe 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 (GRS(CRP)), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRS(GWAS)). 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 GRS(CRP) and GRS(GWAS), respectively. CRP GRS(GWAS) 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 x 10(-6)). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 x 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 x 10(-4)) showed a statistically significant (p <2.45 x 10(-4)) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRS(GWAS) 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 x 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 m(2) (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.ConclusionsGenetically 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 GRS(CRP) or GRS(GWAS)-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.

KW - GENOME-WIDE ASSOCIATION

KW - CORONARY-HEART-DISEASE

KW - BODY-MASS INDEX

KW - ALL-CAUSE MORTALITY

KW - CARDIOVASCULAR-DISEASE

KW - COMMON VARIANTS

KW - BIPOLAR DISORDER

KW - GENETIC-VARIANTS

KW - RISK LOCI

KW - SUSCEPTIBILITY LOCUS

U2 - 10.1371/journal.pmed.1001976

DO - 10.1371/journal.pmed.1001976

M3 - Article

VL - 13

JO - PLOS MEDICINE

JF - PLOS MEDICINE

SN - 1549-1277

IS - 6

M1 - e1001976

ER -

ID: 33305332