To our knowledge, this is the first study to have investigated relationships of smoking initiation, heaviness of smoking and smoking cessation with aggregate measures of genetic risk for major psychiatric disorders and intelligence in older adults from the general population in the UK. Cumulatively, our results demonstrate that smoking is the behaviour that does not appear to share common genetic markers with schizophrenia, bipolar disorders, and intelligence. Whereas moderate to heavy smoking is associated with the additive effects of genetic factors associated with major depressive disorders, reiterating an assertion that the genetic risks captured with polygenic scores influence response to nicotine and not the propensity to initiate smoking[12].
Two-thirds of all adults in our cohort reported smoking at some point during their lives, with 13.5% of these being moderate to heavy smokers. Stopping smoking in old ages have several proven benefits including a reduced morbidity and lower mortality risk. For example, it has been shown that having stopped smoking at the age of 65 and over led to statistically significant reduction in risk of all-cause mortality in the following 1–2 years and approached that of never-smokers after 15–20 years[28, 29]. This recognition ignited significant efforts in encouraging public in the UK to stop smoking through offering free smoking cessation services staffed by expert advisers as well as targeting workplace tobacco control interventions[30]. Although surveys have indicated that a large proportion of elderly smokers would like to quit[3], our results showed that 22.5% adults with an arrange age of 64.8 years old remained smokers, which is consistent with the national estimates of smoking-related behaviours[1].
It was previously shown that smoking initiation and schizophrenia diagnosis shared a substantial component of common genetic variation shared between [19, 20]. However, in the present study, older adults who were smokers did not differ in their polygenic predisposition to schizophrenia from adults who never smoked. We further considered that high genetic predisposition either to bipolar disorders, major depressive disorders, or intelligence might be associated with smoking initiation in older adults. Once again, our findings were negative. In contrast to our findings, using a sample of n = 144609 Icelandic individuals, it was previously shown that there was a common genetic variation that was shared between smoking initiation and schizophrenia and bipolar disorders[20]. It is noteworthy that the polygenic scores utilised in that study were computed from smaller summary statistics for schizophrenia (36989 cases and 113075 controls) and bipolar disorders (7481 cases and 9250 controls) compared to polygenic scores used in the present study. Indeed, our power calculation showed that polygenic score for schizophrenia employed in the present analyses was substantially more powerful explaining 13.5% of the variance in schizophrenia (p = 3.89×10− 213); though, the polygenic score for bipolar disorders employed in the present study was comparable to the previous report[20]. Thus, it is feasible that the differences in the results, at least in relation to polygenic predisposition to schizophrenia, may be due to powers accumulated in PGSs across studies. While there is a genetic correlation between smoking behaviours and schizophrenia[19], our results may imply that this correlation does not express into the actual behavioural trait in older adults.
There is a growing support for an association between smoking and depression; though, there is no consensus on the nature of this relationship. On one hand it is feasible that smoking causes depression onset, on the other, it has been argued that depression causes smoking initiation[31] by means of relieving symptoms related to depression or reduction of the side effects of psychopharmacological treatments[32]. Our results showed that having started to smoke, older adults with a higher polygenic predisposition to major depressive disorders were more likely to become moderate to heavy smokers, which was used as a proxy for nicotine dependence[33]. This is in line with the findings from Virginia Twin Registry suggesting that genetic factors associated with an increased risk for depression overlap with those that convey risk for daily smoking[34]. Our results further reiterate that familial vulnerability to depression, even in the absence of any history of depression, is likely to increase vulnerability to progressing to heavier smoking[35].
Similarly, to smoking initiation, we did not observe significant relationships of polygenic predisposition to schizophrenia, bipolar disorders, major depression, and intelligence with smoking cessation in older adults. The observed non-significant associations may reflect attrition effects, which are unavoidable in longitudinal cohorts. Similarly, because of the results presented in the study are based on longitudinal study with prospectively collected data, collider bias may have contributed to this finding[36], which might have arisen from selection bias or attrition. Even though comparisons with the national census showed that the ELSA sample was representative of the non-institutionalised general population aged ≥ 50 residing in the UK[37], to ensure we completely minimised any issues related to the selection bias we used inverse probability weighting in our models[38]. It is further feasible that single genetic markers for schizophrenia, bipolar disorders, major depression, and intelligence of large effect, rather than an aggerate of common genetic markers of small effect, influences the risk of smoking initiations in the general population. For example, one of the robust schizophrenia associated loci identified by a large genome-wide association study meta-analysis[17] has been found in a gene cluster encoding neuronal nicotinic acetylcholine receptors (nAChR), which is linked to heaviness of smoking in the general population[10, 39]. However, by design, polygenic scores do not capture other structural variants beyond common genetic markers of relatively small effects, such as rare variants, poorly tagged or multiple independent variants, gene-by-gene interactions and gene-environment correlations[40]. Nonetheless, our results have clear implications for public health; specifically because smoking initiation and cessation do not appear to be behaviours that share a common genetic ground with schizophrenia, bipolar disorders, major depression, and intelligence, it may be postulated that these results underscore the importance of smoking preventative campaigns and educational efforts directed towards the public about the harms of smoking.
Limitations
Most smoking is initiated early in life, and the situation of participants may have been rather different then. Another limitation of the current study is that it uses cross-sectional data. Many of the respondents who were not smoking at the time of the survey will have relapsed afterwards. PGSs are fundamentally dependent on the availability of the summary statistics from genome-wide association studies, which are currently predominately based on European participants[41]. Therefore, it is essential to develop PGSs models in non-white populations before the results could be generalised to the whole population. Although we assessed several associations, which may raise some concerns over multiple statistical testing, our sample size was large enough to withstand multiple testing without increasing risk for false positive results. N fact, it has been argued that adjusting for multiple statistical testing has significant disadvantages[42]. Consequently, rather than adjusting our p-values for multiple-testing, we followed the new guidelines for statistical reporting[43] when presenting our results.