Genetic Relationship between Schizophrenia and Nicotine Dependence

Abstract

It is well known that most schizophrenia patients smoke cigarettes. There are different hypotheses postulating the underlying mechanisms of this comorbidity. We used summary statistics from large meta-analyses of plasma cotinine concentration (COT), Fagerström test for nicotine dependence (FTND) and schizophrenia to examine the genetic relationship between these traits. We found that schizophrenia risk scores calculated at P-value thresholds of 5 × 10−3 and larger predicted FTND and cigarettes smoked per day (CPD), suggesting that genes most significantly associated with schizophrenia were not associated with FTND/CPD, consistent with the self-medication hypothesis. The COT risk scores predicted schizophrenia diagnosis at P-values of 5 × 10−3 and smaller, implying that genes most significantly associated with COT were associated with schizophrenia. These results implicated that schizophrenia and FTND/CPD/COT shared some genetic liability. Based on this shared liability, we identified multiple long non-coding RNAs and RNA binding protein genes (DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, DA902558, RBFOX1 and TINCR), protein modification genes (MANBA, UBE2D3, and RANGAP1) and energy production genes (XYLB, MTRF1 and ENOX1) that were associated with both conditions. Further analyses revealed that these shared genes were enriched in calcium signaling, long-term potentiation and neuroactive ligand-receptor interaction pathways that played a critical role in cognitive functions and neuronal plasticity.

Association Between Substance Use Disorder and Polygenic Liability to Schizophrenia

“…In general, the associations became stronger overall with less restrictive p-value cutoffs, which is consistent with previous studies (22, 23). In the mega-analysis, the association between any substance use disorder and schizophrenia polygenic risk score peaked at p T <0.5; pseudo R 2 range 0.8% to 3.7%, minimum p = 4×10 −23 .…”

“…Our data suggest that when testing the relationship between a substance-related phenotype and the polygenic risk score for schizophrenia, the diagnosis of any substance use disorder may be the most informative substance-related phenotype to use, especially with a heterogeneously ascertained series of samples. Despite this, we would expect that analyses with large enough sample sizes, as in the study reported by Chen et al (22), will detect attenuated associations between the schizophrenia polygenic risk score and individual substance use disorder. These findings highlight the power of carefully ascertained smaller samples where precise phenotyping can provide useful insights (and large effect sizes) that may not otherwise be seen.…”

“…Our results show that this approach of combining many different datasets with varying ascertainment schema may temper associations. For example, Chen et al (22) found a much weaker association of nicotine dependence and cigarettes per day with a similarly generated polygenic risk score for schizophrenia in a large meta-analysis of samples ascertained as population and disease-based cohorts (R 2 ≤ 0.1%, N=13,326). Our data suggest that when testing the relationship between a substance-related phenotype and the polygenic risk score for schizophrenia, the diagnosis of any substance use disorder may be the most informative substance-related phenotype to use, especially with a heterogeneously ascertained series of samples.…”

“…We recently found a statistically significant association between general liability for substance use disorder and polygenic risk for cross-disorder psychopathology (19). In addition, recent studies have described common genetic risk factors between schizophrenia and cannabis use (20, 21), and evidence for shared genetic factors between schizophrenia and smoking-related phenotypes (22, 23). …”

Temporal trends in cardiovascular disease risk factor profiles in a population-based schizophrenia sample: a repeat cross-sectional study

“…However, a recent US study suggests that smoking rates have declined significantly less among adults with mental illness than those without 36. Similarly, our findings suggest that public health efforts to reduce smoking in the general population may not have been as effective for those with schizophrenia who may require more targeted clinical interventions, especially given that schizophrenia itself may be associated biologically with an increased risk for nicotine dependence 37. Focused interventions and prevention strategies to target obesity and smoking in high-risk groups, such as those with serious mental illness, are therefore warranted.…”