Genetic correlation between smoking behaviors and schizophrenia
Introduction
Severe mental illness and nicotine dependence frequently co-occur. Individuals suffering from schizophrenia have much higher rates of smoking than the general population (Hartz et al., 2014) and smokers are more likely to suffer from schizophrenia (Gage et al., 2014, Gurillo et al., 2015, Myles et al., 2012, Sorensen et al., 2011, Zammit et al., 2003). Furthermore, much of the morbidity and premature mortality in individuals with schizophrenia can be attributed to smoking-related diseases (Brady et al., 1993, Colton and Manderscheid, 2006, Crump et al., 2013, Drake and Wallach, 1989, Olfson et al., 2015, Parks et al., 2006).
Given the severe public health consequences of the comorbidity of schizophrenia with nicotine dependence, understanding the etiology of this comorbidity is clinically important. Currently, schizophrenia is diagnosed and treated independently of nicotine dependence. Prognostically, there is already evidence that schizophrenia with comorbid nicotine dependence is more severe and has worse outcomes than schizophrenia without comorbid nicotine dependence (Gage et al., 2014, Sorensen et al., 2011, Tsoi et al., 2013, Zammit et al., 2003).
There are three non-exclusive models to explain the comorbidity between nicotine dependence and schizophrenia (Gage and Munafo, 2015a): (1) smoking may lead to the onset of schizophrenia; (2) schizophrenia may cause the development of nicotine dependence (self-medication, for example); and (3) there may be common underlying risk factors, environmental and genetic, that predispose to both schizophrenia and nicotine dependence. Recently, there has been growing evidence to suggest a causal pathway from smoking to schizophrenia. Studies have found that smoking prospectively predicts risk for schizophrenia (Gage et al., 2014, Kendler et al., 2015). Further, the observed association did not arise from smoking onset during the prodromal period of schizophrenia and demonstrated a clear dose-response relationship (Kendler et al., 2015).
There is new evidence that nicotine dependence and schizophrenia share contributory genetic factors. Recently, the Psychiatric Genetics Consortium identified 128 independent loci that contribute to the risk of developing schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). Interestingly, one locus recently identified as contributing to schizophrenia is the chromosome 15q24 locus, which contains the α5-α3-β4 nicotinic receptor subunit genes and is the strongest genetic contributor to nicotine dependence (Hancock et al., 2015, TAG, 2010). Although this is promising evidence of shared genetic factors between nicotine dependence and schizophrenia, because the analysis did not adjust for smoking, the finding may be due to confounding from smoking. A different study found positive associations both between nicotine dependence and polygenic risk scores for schizophrenia, and between schizophrenia and polygenic risk scores for cotinine levels (Chen et al., 2016). These complimentary analyses support the hypothesis that nicotine dependence and schizophrenia have shared genetic factors. However, additional studies are needed to clarify this relationship.
One approach to determining whether shared genetic factors contribute to multiple phenotypes is to estimate the genetic correlation between the phenotypes using linkage disequilibrium (LD) score regression (Bulik-Sullivan et al., 2015a, Bulik-Sullivan et al., 2015b). Using known LD between single nucleotide polymorphisms (SNPs), the intercept computed from LD score regression can be included in GWAS analyses as a powerful correction factor for the inflation of test statistics (Bulik-Sullivan et al., 2015b). In addition, the formula for LD score regression can be permuted to compute the genetic correlation between phenotypes based on GWAS results, termed genetic correlation (Bulik-Sullivan et al., 2015a).
LD score regression has been used to show genetic correlation between multiple psychiatric phenotypes (Bulik-Sullivan et al., 2015a), which included observed positive genetic correlation between schizophrenia and both the age of onset of smoking and cigarettes smoked per day (p < 0.05). However, to our knowledge, the genetic correlation between the full complement of smoking behaviors (including nicotine dependence) and schizophrenia has not been fully characterized. In this study, we use LD score regression to evaluate the genetic correlation between multiple smoking phenotypes and schizophrenia.
Section snippets
Smoking phenotypes
To evaluate the genetic correlation between smoking phenotypes and schizophrenia, five different smoking phenotypes were used (Table 1). Ever/never smoker was coded as a dichotomous phenotype, with ever smokers typically defined as having smoked 100 cigarettes lifetime (Tobacco and Genetics Consortium, 2010). Age of onset of smoking was a continuous phenotype that was log transformed for analysis, and was defined as the age of onset of regular smoking (Tobacco and Genetics Consortium, 2010).
Results
The first step was to estimate the heritability of the smoking phenotypes. The univariate SNP heritability, the proportion of phenotypic variance explained by GWAS SNPs, was evaluated for each smoking phenotype (Table 2). All the smoking phenotypes have statistically significant SNP heritability (p < 0.001). The phenotype with the highest magnitude of estimated SNP heritability (15%) was nicotine dependence. This is approximately double the estimated SNP heritability for the other smoking
Discussion
The results of this study show that (1) common genetic variation explains more phenotypic variance for nicotine dependence relative to other smoking phenotypes (i.e. higher SNP heritability), and (2) there is a component of common genetic variation that is shared between smoking behaviors and schizophrenia (i.e. nonzero genetic correlation).
LD score regression has identified multiple diseases that have shared genetic factors with schizophrenia (Bulik-Sullivan et al., 2015a). Of these, bipolar
Conflict of interest
All authors declare that they have no conflicts of interest.
Contributors
Drs. Hartz and Bierut designed the study and wrote the protocol. Drs. Hartz, Horton and Bierut designed and conducted statistical analyses. All authors contributed to data harmonization and interpretation of results. Dr. Hartz wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Role of funding source
This study was funded by the NIH. The funding source had no role in the study design and analysis.
Acknowledgements
We thank the many participants of these studies. This work was supported by the National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA) grant numbers K08 032680, R01 DA035825, R01 DA036583, R01 HL089897, R01 HL089856, K01 HL125858, R01-DE014899 and U01-DE018903. Funding support for the nicotine dependence study samples were previously described (Hancock et al., 2015). The content is solely the responsibility of the authors and does not necessarily represent the views of the
References (38)
- et al.
Rethinking the association between smoking and schizophrenia
The lancet. Psychiatry
(2015) - et al.
Smoking as a causal risk factor for schizophrenia
The lancet. Psychiatry
(2015) - et al.
Does tobacco use cause psychosis? Systematic review and meta-analysis
The Lancet Psychiatry
(2015) - et al.
A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma
Am. J. Hum. Genet.
(2009) - et al.
Time to first cigarette in the morning as an index of ability to quit smoking: implications for nicotine dependence
Nicotine Tob. Res.
(2007) - et al.
Novel genes identified in a high-density genome wide association study for nicotine dependence
Hum. Mol. Genet.
(2007) - et al.
Depression in alcoholic schizophrenic patients
Am. J. Psychiatry
(1993) - et al.
An atlas of genetic correlations across human diseases and traits
Nat. Genet.
(2015) - et al.
LD Score regression distinguishes confounding from polygenicity in genome-wide association studies
Nat. Genet.
(2015) - et al.
Dissection of the phenotypic and genotypic associations with nicotinic dependence
Nicotine Tob. Res.
(2012)