Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium

Abstract

<jats:title>Abstract</jats:title><jats:p>Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci <jats:italic>MAGI2/GNAI1</jats:italic> (rs2714700) and <jats:italic>TENM2</jats:italic> (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were <jats:italic>cis</jats:italic>-eQTLs (rs2714700 for <jats:italic>MAGI2-AS3</jats:italic> in hippocampus, rs1862416 for <jats:italic>TENM2</jats:italic> in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 17 other smoking traits (r<jats:sub>g</jats:sub>=0.40–0.95) and co-morbidities. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.</jats:p>

Genetic architecture of four smoking behaviors using partitioned h2SNP

“…In this case, though lacking other important aspects of the clinical presentation such as craving or loss of control, the dichotomized heavy/light phenotype is comparing individuals who may find overnight abstinence less aversive and start smoking later in the day, and endorse lower levels of nicotine dependence (light) to those who meet criteria for severe nicotine dependence (heavy), whereas the standard continuous CPD encoding includes intermediate levels of smoking heaviness that may or may not correlate with clinical presentations of nicotine dependence. Our GREML-based estimate of common, well-tagged h 2 SNP (∼0.09) is approximately the same as one recently reported LDSC-based estimate of nicotine dependence(15), consistent with this hypothesis.…”

“…While additional common variants of very small effect are likely to be identified as sample sizes grow, some of the unexplained variability undoubtedly arises from uncommon and rare variants (MAF<0.01), though their relative contribution is uncertain. The most recent large GWASs(11, 15) of smoking behaviors and nicotine dependence, using LD score regression (LDSC), estimate the SNP-based heritability ( h 2 SNP ) due to common variants as 0.05-0.09 across traits(16). A related exome sequencing study(17) estimated that rare coding variants explained approximately 1-2% of the phenotypic variance.…”

“…Furthermore, the allele frequency spectrum and contribution of functional annotations related to LD, allele frequency, recombination and related genomic features for smoking behaviors has not been fully explored. One study applied partitioned h 2 SNP approaches to evaluate tissue-specific effects, with results indicating that genes expressed in the cerebellum are enriched in their contribution to nicotine dependence(15). The only published work has examined a single trait, smoking status, finding contributions of low-LD and -MAF variants consistent with negative or purifying selection(20, 21).…”

Polygenic Score for Smoking Is Associated With Externalizing Psychopathology and Disinhibited Personality Traits but Not Internalizing Psychopathology in Adolescence

“…One useful application of PGSs is the ability to draw the boundaries of genetic influences on psychiatric disorders. For example, there is significant overlap among PGSs for schizophrenia, bipolar, autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), and major depression (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013a, 2013b) and among alcohol, nicotine, and cannabis use (Liu et al, 2019;Quach et al, 2020;Zhou et al, 2019), and there is some evidence of genetic specificity (Byrne et al, 2021). Relatedly, childhood symptoms are associated with PGSs for adult disorders, indicating that these genetic influences contribute to the expression of psychiatric problems early in life.…”

Novel insights into the common heritable liability to addiction: a multivariate genome-wide association study

“…Other variants may affect common pathways, such as variants associating with two or more classes of psychoactive substances (e.g. BDNF 7,19,20 , PDE4B 7,20,21 or DRD2 7,15,18,20,22 ) or behavioural phenotypes (e.g., the top variant identified for cannabis use disorder, which also associates with ADHD and risk-taking 23 ).…”