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Genetic susceptibility for schizophrenia after adjustment by genetic susceptibility for smoking: implications in identification of risk genes and genetic correlation with related traits

Published online by Cambridge University Press:  06 March 2023

Laila Al-Soufi Open the ORCID record for Laila Al-Soufi [Opens in a new window]  and
Javier Costas Open the ORCID record for Javier Costas [Opens in a new window]
Laila Al-Soufi
Affiliation:
Psychiatric Genetics group, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Galicia, Spain Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Spain Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Galicia, Spain
Javier Costas*
Affiliation:
Psychiatric Genetics group, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Galicia, Spain Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Spain Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Galicia, Spain
*
Author for correspondence: Javier Costas, E-mail: javier.costas.costas@sergas.es
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Abstract

Background

Prevalence of smoking in schizophrenia (SCZ) is larger than in general population. Genetic studies provided some evidence of a causal effect of smoking on SCZ. We aim to characterize the genetic susceptibility to SCZ affected by genetic susceptibility to smoking.

Methods

Multi-trait-based conditional and joint analysis was applied to the largest European SCZ genome-wide association studies (GWAS) to remove genetic effects on SCZ driven by smoking, estimated by generalized summary data-based Mendelian randomization. Enrichment analysis was performed to compare original v. conditional GWAS. Change in genetic correlation between SCZ and relevant traits after conditioning was assessed. Colocalization analysis was performed to identify specific loci confirming general findings.

Results

Conditional analysis identified 19 new risk loci for SCZ and 42 lost loci whose association with SCZ may be partially driven by smoking. These results were strengthened by colocalization analysis. Enrichment analysis indicated a higher association of differentially expressed genes at prenatal brain stages after conditioning. Genetic correlation of SCZ with substance use and dependence, attention deficit-hyperactivity disorder, and several externalizing traits significantly changed after conditioning. Colocalization of association signal between SCZ and these traits was identified for some of the lost loci, such as CHRNA2, CUL3, and PCDH7.

Conclusions

Our approach led to identification of potential new SCZ loci, loci partially associated to SCZ through smoking, and a shared genetic susceptibility between SCZ and smoking behavior related to externalizing phenotypes. Application of this approach to other psychiatric disorders and substances may lead to a better understanding of the role of substances on mental health.

Keywords

Colocalizationexternalizing behaviorimpulsivitypleiotropypsychopathologyrisk-taking behaviorschizophreniashared genetic susceptibilitysmokingsubstance use
Type
Original Article
Information
Psychological Medicine , Volume 53 , Issue 14 , October 2023 , pp. 6806 - 6816
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Copyright
Copyright © The Author(s), 2023. Published by Cambridge University Press

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References

Alnæs, D., Kaufmann, T., Van Der Meer, D., Córdova-Palomera, A., Rokicki, J., Moberget, T., … Westlye, L. T. (2019). Brain heterogeneity in schizophrenia and its association with polygenic risk. JAMA Psychiatry, 76(7), 739–748. https://doi.org/10.1001/jamapsychiatry.2019.0257.CrossRefGoogle ScholarPubMed
Al-Soufi, L., & Costas, J. (2021). Colocalization of association signals at nicotinic acetylcholine receptor genes between schizophrenia and smoking traits. Drug and Alcohol Dependence, 220, 108517. https://doi.org/10.1016/j.drugalcdep.2021.108517.CrossRefGoogle ScholarPubMed
Al-Soufi, L., Martorell, L., Moltó, M. D., González-Peñas, J., García-Portilla, M. P., Arrojo, M., … Costas, J. (2022). A polygenic approach to the association between smoking and schizophrenia. Addiction Biology, 27(1), 1–10. https://doi.org/10.1111/adb.13104.CrossRefGoogle Scholar
Barkhuizen, W., Dudbridge, F., & Ronald, A. (2021). Genetic overlap and causal associations between smoking behaviours and mental health. Scientific Reports, 11(1), 1–13. https://doi.org/10.1038/s41598-021-93962-7.CrossRefGoogle ScholarPubMed
Bobes, J., Arango, C., Garcia-Garcia, M., & Rejas, J. (2010). Healthy lifestyle habits and 10-year cardiovascular risk in schizophrenia spectrum disorders: An analysis of the impact of smoking tobacco in the CLAMORS schizophrenia cohort. Schizophrenia Research, 119(1–3), 101–109. https://doi.org/10.1016/j.schres.2010.02.1030.CrossRefGoogle ScholarPubMed
Bulik-Sullivan, B., Finucane, H. K., Anttila, V., Gusev, A., Day, F. R., Loh, P.-R., … Neale, B. M. (2015). An atlas of genetic correlations across human diseases and traits. Nature Genetics, 47(11), 1236–1241. https://doi.org/10.1038/ng.3406.CrossRefGoogle ScholarPubMed
Byrne, E. M., Ferreira, M. A. R., Xue, A., Lindström, S., Jiang, X., Yang, J., … Chenevix-Trench, G. (2019). Is schizophrenia a risk factor for breast cancer?-evidence from genetic data. Schizophrenia Bulletin, 45(6), 1251–1256. https://doi.org/10.1093/schbul/sby162.CrossRefGoogle ScholarPubMed
Byrne, E. M., Zhu, Z., Qi, T., Skene, N. G., Bryois, J., Pardinas, A. F., … Wray, N. R. (2021). Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders. Molecular Psychiatry, 26(6), 2070–2081. https://doi.org/10.1038/s41380-020-0705-9.CrossRefGoogle ScholarPubMed
Cai, N., Revez, J. A., Adams, M. J., Andlauer, T. F. M., Breen, G., Byrne, E. M., … Flint, J. (2020). Minimal phenotyping yields genome-wide association signals of low specificity for major depression. Nature Genetics, 52(4), 437–447. https://doi.org/10.1038/s41588-020-0594-5.CrossRefGoogle ScholarPubMed
Catania, E. H., Pimenta, A., & Levitt, P. (2008). Genetic deletion of Lsamp causes exaggerated behavioral activation in novel environments. Behavioural Brain Research, 188(2), 380–390. https://doi.org/10.1016/j.bbr.2007.11.022.Google ScholarPubMed
Creamer, M. R., Wang, T. W., Babb, S., Cullen, K. A., Day, H., Willis, G., … Neff, L. (2019). Tobacco product use and cessation indicators among adults – United States, 2018. MMWR. Morbidity and Mortality Weekly Report, 68(45), 1013–1019. https://doi.org/10.15585/mmwr.mm6845a2.CrossRefGoogle Scholar
Davies, N. M., Holmes, M. V., & Davey Smith, G. (2018). Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ, 362, k601. https://doi.org/10.1136/bmj.k601.CrossRefGoogle ScholarPubMed
Demontis, D., Rajagopal, V. M., Thorgeirsson, T. E., Als, T. D., Grove, J., Leppälä, K., … Børglum, A. D. (2019). Genome-wide association study implicates CHRNA2 in cannabis use disorder. Nature Neuroscience, 22(7), 1066–1074. https://doi.org/10.1038/s41593-019-0416-1.CrossRefGoogle ScholarPubMed
Dervaux, A., Baylé, F. J., Laqueille, X., Bourdel, M., Le Borgne, M.-H., Olié, J., & Krebs, M. (2001). Is substance abuse in schizophrenia related to impulsivity, sensation seeking, or anhedonia? American Journal of Psychiatry, 158(3), 492–494. https://doi.org/10.1176/appi.ajp.158.3.492.CrossRefGoogle ScholarPubMed
Dir, A. L., & Hulvershorn, L. A. (2019). Sex differences in adolescent neurobiological risk for substance use and substance use disorders. Current Addiction Reports, 6(4), 514–521. https://doi.org/10.1007/s40429-019-00276-w.CrossRefGoogle Scholar
Firth, J., Wootton, R. E., Sawyer, C., & Taylor, G. M. (2023). Clearing the air: Clarifying the causal role of smoking in mental illness. World Psychiatry, 22(1), 151–152. https://doi.org/10.1002/wps.21023.CrossRefGoogle ScholarPubMed
Fischer, B. A., McMahon, R. P., Kelly, D. L., Wehring, H. J., Meyer, W. A., Feldman, S., … Gorelick, D. A. (2015). Risk-taking in schizophrenia and controls with and without cannabis dependence. Schizophrenia Research, 161(2–3), 471–477. https://doi.org/10.1016/j.schres.2014.11.009.CrossRefGoogle ScholarPubMed
Gage, S. H., & Munafò, M. R. (2015). Rethinking the association between smoking and schizophrenia. The Lancet Psychiatry, 2(2), 118–119. https://doi.org/10.1016/S2215-0366(14)00057-1.CrossRefGoogle ScholarPubMed
Goff, D. C., Henderson, D. C., & Amico, E. (1992). Cigarette smoking in schizophrenia: Relationship to psychopathology and medication side effects. American Journal of Psychiatry, 149(9), 1189–1194. https://doi.org/10.1176/ajp.149.9.1189.Google ScholarPubMed
Green, V. R., Conway, K. P., Silveira, M. L., Kasza, K. A., Cohn, A., Cummings, K. M., … Compton, W. M. (2018). Mental health problems and onset of tobacco use among 12- to 24-year-olds in the PATH study. Journal of the American Academy of Child & Adolescent Psychiatry, 57(12), 944–954. e4. https://doi.org/10.1016/j.jaac.2018.06.029.CrossRefGoogle ScholarPubMed
Griffith, J. W., Zinbarg, R. E., Craske, M. G., Mineka, S., Rose, R. D., Waters, A. M., & Sutton, J. M. (2010). Neuroticism as a common dimension in the internalizing disorders. Psychological Medicine, 40(7), 1125–1136. https://doi.org/10.1017/S0033291709991449.CrossRefGoogle ScholarPubMed
Gurillo, P., Jauhar, S., Murray, R. M., & MacCabe, J. H. (2015). Does tobacco use cause psychosis? Systematic review and meta-analysis. The Lancet Psychiatry, 2(8), 718–725. https://doi.org/10.1016/S2215-0366(15)00152-2.CrossRefGoogle ScholarPubMed
Gut-Fayand, A., Dervaux, A., Olié, J. P., Lôo, H., Poirier, M. F., & Krebs, M. O. (2001). Substance abuse and suicidality in schizophrenia: A common risk factor linked to impulsivity. Psychiatry Research, 102(1), 65–72. https://doi.org/10.1016/S0165-1781(01)00250-5.CrossRefGoogle ScholarPubMed
Heerey, E. A., Robinson, B. M., McMahon, R. P., & Gold, J. M. (2007). Delay discounting in schizophrenia. Cognitive Neuropsychiatry, 12(3), 213–221. https://doi.org/10.1080/13546800601005900.CrossRefGoogle ScholarPubMed
Heitzeg, M. M., Hardee, J. E., & Beltz, A. M. (2018). Sex differences in the developmental neuroscience of adolescent substance use risk. Current Opinion in Behavioral Sciences, 23, 21–26. https://doi.org/10.1016/j.cobeha.2018.01.020.CrossRefGoogle ScholarPubMed
Hill, W. D., Davies, N. M., Ritchie, S. J., Skene, N. G., Bryois, J., Bell, S., … Deary, I. J. (2019). Genome-wide analysis identifies molecular systems and 149 genetic loci associated with income. Nature Communications, 10(1), 1–16. https://doi.org/10.1038/s41467-019-13585-5.CrossRefGoogle ScholarPubMed
Hindley, G., Bahrami, S., Steen, N. E., O'Connell, K. S., Frei, O., Shadrin, A., … Andreassen, O. A. (2021). Characterising the shared genetic determinants of bipolar disorder, schizophrenia and risk-taking. Translational Psychiatry, 11(1), 1–10. https://doi.org/10.1038/s41398-021-01576-4.CrossRefGoogle ScholarPubMed
Hindley, G., Frei, O., Shadrin, A. A., Cheng, W., O'Connell, K. S., Icick, R., … Andreassen, O. A. (2022). Charting the landscape of genetic overlap between mental disorders and related traits beyond genetic correlation. American Journal of Psychiatry, 179(11), 833–843. https://doi.org/10.1176/appi.ajp.21101051.CrossRefGoogle ScholarPubMed
Hunter, A., Murray, R., Asher, L., & Leonardi-Bee, J. (2020). The effects of tobacco smoking, and prenatal tobacco smoke exposure, on risk of schizophrenia: A systematic review and meta-analysis. Nicotine & Tobacco Research, 22(1), 3–10. https://doi.org/10.1093/ntr/nty160.CrossRefGoogle ScholarPubMed
Jablensky, A. (2006). Subtyping schizophrenia: Implications for genetic research. Molecular Psychiatry, 11(9), 815–836. https://doi.org/10.1038/sj.mp.4001857.CrossRefGoogle ScholarPubMed
Johnson, E. C., Hatoum, A. S., Deak, J. D., Polimanti, R., Murray, R. M., Edenberg, H. J., … Agrawal, A. (2021). The relationship between cannabis and schizophrenia: A genetically informed perspective. Addiction, 116(11), 3227–3234. https://doi.org/10.1111/add.15534.CrossRefGoogle ScholarPubMed
Kahn, R. S., Sommer, I. E., Murray, R. M., Meyer-Lindenberg, A., Weinberger, D. R., Cannon, T. D., … Insel, T. R. (2015). Schizophrenia. Nature Reviews Disease Primers, 1(1), 15067. https://doi.org/10.1038/nrdp.2015.67.CrossRefGoogle ScholarPubMed
Karlsson Linnér, R., Mallard, T. T., Barr, P. B., Sanchez-Roige, S., Madole, J. W., Driver, M. N., … Dick, D. M. (2021). Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction. Nature Neuroscience, 24(10), 1367–1376. https://doi.org/10.1038/s41593-021-00908-3.CrossRefGoogle ScholarPubMed
Kendler, K. S., Lönn, S. L., Sundquist, J., & Sundquist, K. (2015). Smoking and schizophrenia in population cohorts of Swedish women and men: A prospective co-relative control study. American Journal of Psychiatry, 172(11), 1092–1100. https://doi.org/10.1176/appi.ajp.2015.15010126.CrossRefGoogle Scholar
Koyanagi, A., Stickley, A., & Haro, J. M. (2016). Psychotic symptoms and smoking in 44 countries. Acta Psychiatrica Scandinavica, 133(6), 497–505. https://doi.org/10.1111/acps.12566.CrossRefGoogle ScholarPubMed
Kumari, V., & Postma, P. (2005). Nicotine use in schizophrenia: The self medication hypotheses. Neuroscience & Biobehavioral Reviews, 29(6), 1021–1034. https://doi.org/10.1016/j.neubiorev.2005.02.006.CrossRefGoogle ScholarPubMed
Lawlor, D. A., Tilling, K., & Smith, G. D. (2016). Triangulation in aetiological epidemiology. International Journal of Epidemiology, 45(6), 1866–1886. https://doi.org/10.1093/ije/dyw314.Google ScholarPubMed
Lee, P. H., Anttila, V., Won, H., Feng, Y-C. A., Rosenthal, J., Zhu, Z., … Smoller, J. W. (2019). Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell, 179(7), 1469–1482.e11. http://dx.doi.org/10.1016/j.cell.2019.11.020.CrossRefGoogle Scholar
Liu, M., Jiang, Y., Wedow, R., Li, Y., Brazel, D. M., Chen, F., … Vrieze, S. (2019). Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nature Genetics, 51(2), 237–244. https://doi.org/10.1038/s41588-018-0307-5.CrossRefGoogle ScholarPubMed
Mullins, N., Kang, J. E., Campos, A. I., Coleman, J. R. I., Edwards, A. C., Galfalvy, H., … Willour, V. (2022). Dissecting the shared genetic architecture of suicide attempt, psychiatric disorders, and known risk factors. Biological Psychiatry, 91(3), 313–327. https://doi.org/10.1016/j.biopsych.2021.05.029.CrossRefGoogle ScholarPubMed
Niemelä, S., Sourander, A., Surcel, H.-M., Hinkka-Yli-Salomäki, S., McKeague, I. W., Cheslack-Postava, K., & Brown, A. S. (2016). Prenatal nicotine exposure and risk of schizophrenia among offspring in a national birth cohort. American Journal of Psychiatry, 173(8), 799–806. https://doi.org/10.1176/appi.ajp.2016.15060800.CrossRefGoogle Scholar
Nolan, K. A., D'Angelo, D., & Hoptman, M. J. (2011). Self-report and laboratory measures of impulsivity in patients with schizophrenia or schizoaffective disorder and healthy controls. Psychiatry Research, 187(1–2), 301–303. https://doi.org/10.1016/j.psychres.2010.10.032.CrossRefGoogle ScholarPubMed
O'dushlaine, C., Rossin, L., Lee, P. H., Duncan, L., Parikshak, N. N., Newhouse, S., … Breen, G. (2015). Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nature Neuroscience, 18(2), 199–209. https://doi.org/10.1038/nn.3922.Google Scholar
Ohlsson, H., & Kendler, K. S. (2020). Applying causal inference methods in psychiatric epidemiology. JAMA Psychiatry, 77(6), 637. https://doi.org/10.1001/jamapsychiatry.2019.3758.CrossRefGoogle ScholarPubMed
Okbay, A., Wu, Y., Wang, N., Jayashankar, H., Bennett, M., Nehzati, S. M., … Young, A. I. (2022). Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals. Nature Genetics, 54(4), 437–449. https://doi.org/10.1038/s41588-022-01016-z.CrossRefGoogle ScholarPubMed
Ouzir, M. (2013). Impulsivity in schizophrenia: A comprehensive update. Aggression and Violent Behavior, 18(2), 247–254. https://doi.org/10.1016/j.avb.2012.11.014.CrossRefGoogle Scholar
Pardiñas, A. F., Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., … Walters, J. T. R. (2018). Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics, 50(3), 381–389. https://doi.org/10.1038/s41588-018-0059-2.CrossRefGoogle ScholarPubMed
Philips, M. A., Lilleväli, K., Heinla, I., Luuk, H., Hundahl, C. A., Kongi, K., … Vasar, E. (2015). Lsamp is implicated in the regulation of emotional and social behavior by use of alternative promoters in the brain. Brain Structure and Function, 220(3), 1381–1393. https://doi.org/10.1007/s00429-014-0732-x.CrossRefGoogle ScholarPubMed
Pickrell, J. K., Berisa, T., Liu, J. Z., Ségurel, L., Tung, J. Y., & Hinds, D. A. (2016). Detection and interpretation of shared genetic influences on 42 human traits. Nature Genetics, 48(7), 709–717. https://doi.org/10.1038/ng.3570.CrossRefGoogle ScholarPubMed
Plomin, R., & von Stumm, S. (2022). Polygenic scores: Prediction versus explanation. Molecular Psychiatry, 27(1), 49–52. https://doi.org/10.1038/s41380-021-01348-y.CrossRefGoogle ScholarPubMed
Quinn, P. D., Rickert, M. E., Weibull, C. E., Johansson, A. L. V., Lichtenstein, P., Almqvist, C., … D'Onofrio, B. M. (2017). Association between maternal smoking during pregnancy and severe mental illness in offspring. JAMA Psychiatry, 74(6), 589–596. https://doi.org/10.1001/jamapsychiatry.2017.0456.CrossRefGoogle ScholarPubMed
Reddy, L. F., Lee, J., Davis, M. C., Altshuler, L., Glahn, D. C., Miklowitz, D. J., & Green, M. F. (2014). Impulsivity and risk taking in bipolar disorder and schizophrenia. Neuropsychopharmacology, 39(2), 456–463. https://doi.org/10.1038/npp.2013.218.CrossRefGoogle ScholarPubMed
Reed, Z. E., Wootton, R. E., & Munafò, M. R. (2022). Using Mendelian randomization to explore the gateway hypothesis: Possible causal effects of smoking initiation and alcohol consumption on substance use outcomes. Addiction, 117(3), 741–750. https://doi.org/10.1111/add.15673.CrossRefGoogle ScholarPubMed
Ripke, S., Neale, B. M., Corvin, A., Walters, J. T., Farh, K. H., Holmans, P. A., … O'Donovan, M. C. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511(7510), 421–427. https://doi.org/10.1038/nature13595.Google Scholar
Sagud, M., Mihaljevic Peles, A., & Pivac, N. (2019). Smoking in schizophrenia: Recent findings about an old problem. Current Opinion in Psychiatry, 32(5), 402–408. https://doi.org/10.1097/YCO.0000000000000529.CrossRefGoogle ScholarPubMed
Solovieff, N., Cotsapas, C., Lee, P. H., Purcell, S. M., & Smoller, J. W. (2013). Pleiotropy in complex traits: Challenges and strategies. Nature Reviews Genetics, 14(7), 483–495. https://doi.org/10.1038/nrg3461.CrossRefGoogle ScholarPubMed
Treur, J. L., Munafò, M. R., Logtenberg, E., Wiers, R. W., & Verweij, K. J. H. (2021). Using Mendelian randomization analysis to better understand the relationship between mental health and substance use: A systematic review. Psychological Medicine, 51(10), 1593–1624. https://doi.org/10.1017/S003329172100180X.CrossRefGoogle ScholarPubMed
Trubetskoy, V., Pardiñas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., … O'Donovan, M. C. (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature, 604(7906), 502–508. https://doi.org/10.1038/s41586-022-04434-5.Google Scholar
Watanabe, K., Taskesen, E., Van Bochoven, A., & Posthuma, D. (2017). Functional mapping and annotation of genetic associations with FUMA. Nature Communications, 8(1), 1–10. https://doi.org/10.1038/s41467-017-01261-5.CrossRefGoogle ScholarPubMed
Wootton, R. E., Richmond, R. C., Stuijfzand, B. G., Lawn, R. B., Sallis, H. M., Taylor, G. M. J., … Munafò, M. R. (2020). Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: A Mendelian randomisation study. Psychological Medicine, 50(14), 2435–2443. https://doi.org/10.1017/S0033291719002678.CrossRefGoogle ScholarPubMed
Yang, J., Lee, S. H., Goddard, M. E., & Visscher, P. M. (2011). GCTA: A tool for genome-wide complex trait analysis. American Journal of Human Genetics, 88(1), 76–82. https://doi.org/10.1016/j.ajhg.2010.11.011.CrossRefGoogle ScholarPubMed
Yuan, S., Yao, H., & Larsson, S. C. (2020). Associations of cigarette smoking with psychiatric disorders: Evidence from a two-sample Mendelian randomization study. Scientific Reports, 10(1), 1–9. https://doi.org/10.1038/s41598-020-70458-4.CrossRefGoogle ScholarPubMed
Zhu, Z., Zheng, Z., Zhang, F., Wu, Y., Trzaskowski, M., Maier, R., … Yang, J. (2018). Causal associations between risk factors and common diseases inferred from GWAS summary data. Nature Communications, 9(1), 224. https://doi.org/10.1038/s41467-017-02317-2.CrossRefGoogle ScholarPubMed
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