Supplemental figure 1. Genome-wide plots of P-values for all 17 traits.

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3 Supplemental figure 1. Genome-wide plots of P-values for all 17 traits. Supplemental figure 2. Regional plots for (A) the 10p11.21 NDSS drive/priority locus, (B) the 15q22.2 FTND time to first cigarette (TTF) locus, and (C) the 2q21.2 age of onset of weekly smoking locus. The top panel shows the SNP association results including 20 kb flanking regions from the locus and/or the farthest end of the nearest gene. Arrow indicates the direction of the gene. The bottom panel shows the LD structure of the locus in the study sample (one individual per family, index twin prioritized), including the SNPs in Table 1 as well as all the intermediate SNPs. The boxes are shaded according to D values (darker shading indicated higher LD), and the numbers in the boxes are the r 2 values (empty boxes represent full LD). 1

4 Supplemental table 1. Phenotypic definitions for all 17 included traits. PHENOTYPE DEFINITION 1 DESCRIPTIVE STATISTICS 2 (I) AMOUNT SMOKED CPD Number of cigarettes smoked per day during month of heaviest smoking; eight categories: 1-2, to 40 (19.8) 4 5, 6-10, 11-15, 16-19, 20-25, 26-39, and 40 CPD. 3 Maximum CPD Maximum number of cigarettes ever smoked during one day (24h period) (30.0) (II) SMOKING INITIATION Age at first puff Age (years) at first puff of cigarette ( How old were you the very first time you smoked even a puff 3-54 (13.9) of a cigarette? ). Age at first cigarette Age (years) when first whole cigarette smoked ( How old were you the first time you smoked a 4-54 (15.6) whole cigarette? ). Second cigarette Second cigarette smoked same or next day after first one ( After you first smoked a whole 53.3% cigarette, how long was it before you smoked your second whole cigarette? ). Age of onset of weekly smoking Age (years) when started to smoke weekly ( How old were you when you first smoked a cigarette 6-54 (17.3) at least once a week for at least two months in a row? ). Age of onset of daily smoking Age (years) when one started to smoke daily ( How old were you when you first smoked cigarette 7-54 (18.3) every day or nearly every day for at least two months in a row? ). First time sensation Sensation felt after smoking the first cigarette or first puffs (10.2) (III) NICOTINE DEPENDENCE diagnosis Nicotine dependence by DSM-IV diagnosis ( 3 out of 7 occurring within a year). 53.5% Number of from 0 to (3.0) FTND ( 4) Nicotine dependent if 4 out of 10 points in Fagerström Test for Nicotine Dependence. 50.4% FTND score Fagerström Test for Nicotine Dependence (FTND) score: 0 to 10 points (3.7) FTND time to first cigarette (TTF) Time to first cigarette in the morning (one item of the FTND scale). Five categories: 0-5 min, (3.1) 4 min 6, min 6, min, >60 min. NDSS drive / priority Drive reflects craving, withdrawal, and smoking compulsions; priority reflects preference for (-0.3) smoking over other reinforces. 7 NDSS stereotypy / continuity Continuity reflects the regularity of smoking rate; stereotypy reflects the invariance of smoking (-0.3) NDSS tolerance Tolerance reflects reduced sensitivity to the effects of smoking (-0.1) NDSS sum score Nicotine Dependence Syndrome Scale (NDSS) (Shiffman et al. 2004), sum score as a continuous 0-56 (21.1) variable from 0 to 56. 1, Adapted from Broms U, Wedenoja J, Largeau MR, Korhonen T, Pitkäniemi J, Keskitalo-Vuokko K, et al. Analysis of detailed phenotype profiles reveals CHRNA5-CHRNA3-CHRNB4 gene cluster association with several nicotine dependence traits. Nicotine Tob Res. 2012; 14(6): , Continuous / categorical: min-max (mean); Binary: prevalence (%) 3, CPD constitutes of eight categories: 1-2, 3-5, 6-10, 11-15, 16-19, 20-25, 26-39, 40 CPD. In the statistical analyses of the CPD variable, original categorical observations were replaced with class means of CPD (1.5, 3.5, 8, 13, 17.5, 22.5, 32.5, and 45 cigarettes per day, respectively). Regression coefficients can therefore be interpreted as the average change in number of cigarettes smoked per day when the number of minor allele is increased by one. 4, Weighted arithmetic mean, where weights are determined by class frequencies. 5, Sensation measured as: While smoking your very first cigarettes, did you (1) like the taste or smell of the cigarette, (2) cough, (3) feel dizzy or light-headed, (4) feel more relaxed, (5) get a headache, (6) feel a pleasurable rush or buzz, (7) feel your heart racing, (8) feel nauseated, like vomiting, (9) feel your muscles tremble or become jittery, (10) feel burning in your throat ). Sum score of 10 questions (items #1, #4, and #6 were reverse-scored before summation): 0 points if answered No, 1= A little bit, 2= Some, 3= Quite a bit, 4= A great deal. Cronbach s alpha = , Categorization differs from original four categories (Heatherton et al. Br J Addict 1991; 86: ), i.e., 6-30 minutes is split into 6-15 min and min. In our data set 46% of smokers belong to the group of 6-30 min, and from the smoking behavior point of view there is a significant difference whether one smokes the first cigarette within 6 minutes or 30 minutes from waking up. In this data set 22% of smokers belong to the 6-15 min and 24% to the min group. 7, Factor structure of the NDSS scale with 31 items conditioned for current smoking and CPD >10 generated a three solution (as previously reported in Broms et al. Drug & Alcohol Dependence 2007; 89: 42-51). Factors accounted for 92% of the common variance among items: 1. Drive/Priority, 11 items (Cronbach s alpha (α)=0.88, accounted for 33%); 2. Stereotypy/Continuity, 9 items (α=0.89, accounted for 33%); 3. Tolerance, 5 items (α=0.82, accounted for 26%).

5 Supplemental table 2. Correlations between the studied traits. Correlations were computed as Spearman and polychoric (tetrachoric and point biserial) correlations as appropriate. Numbers of individuals range from 957 to 1114 in pair-wise correlations due to missing data. PHENOTYPE CPD 2 Maximum CPD Age at first puff Age at first cigarette Second cigarette Age at onset of weekly smoking Age at onset of daily smoking First time sensation diagnosis FTND ( 4) FTND score FTND time to first cigarette (TTF) NDSS drive/priority NDSS stereotypy/continuity NDSS tolerance NDSS sum score Correlations measured by Phi Coefficient by R software package psych (Ihaka et al. J Comput Graph Stat 1996; 5: ) as at least one of the combinations of the variables is zero.

6 Supplemental table 3. Trait correlations calculated among monozygotic (MZ) and dizygotic (DZ) twin pairs identified from the Finnish Nicotine Addiction Genetics study sample and heritability estimates from the literature. Heritability estimates Phenotype 1 MZ correlations DZ correlations (116 pairs) (429 pairs) 2 from the literature CPD 0.48 ( ) 0.14 ( ) 40-61% (REF 1 ) Maximum CPD 0.40 ( ) 0.16 ( ) 55% (REF 2 ) Age at first puff 0.63 ( ) 0.21 ( ) N.A. Age at first cigarette 0.50 ( ) 0.20 ( ) 32-78% (REF 1 ) Second cigarette 0.21 ( ) 0.02 ( ) N.A. Age of onset of weekly smoking 0.40 ( ) 0.15 ( ) N.A. Age of onset of daily smoking 0.40 ( ) 0.12 ( ) N.A. First time sensation 0.25 ( ) 0.06 ( ) 37% (REF 3 ) diagnosis 0.12 ( ) 0.07 ( ) 60% (REF 4 ) ( ) 0.12 ( ) 40-75% (REF 1 ) FTND ( 4) 0.32 ( ) 0.17 ( ) 67% (REF 5 ) FTND score 0.51 ( ) 0.19 ( ) 39-75% (REFS 1, 6, 7 ) FTND time to first cigarette (TTF) 0.31 ( ) 0.13 ( ) 68% (REF 8 ) NDSS drive / priority 0.18 ( ) 0.04 ( ) N.S. (REF 9 ) NDSS stereotypy / continuity 0.50 ( ) 0.16 ( ) 44% (REF 9 ) NDSS tolerance 0.37 ( ) 0.19 ( ) 39% (REF 9 ) NDSS sum score 0.44 ( ) 0.05 ( ) 30% (REF 9 ) 1, Phenotype definitions are presented in Supplemental table 1. 2, Includes same-sex and opposite-sex dizygotic twin pairs 3, ND diagnosis based on DSM-IIIR REF 1, Rose J E, Broms U, Korhonen T, Dick DM, Kaprio J. (2009). Genetics of smoking behavior. In Kim YK (Ed.), Handbook of behavior genetics. (1st ed., pp ). New York: Springer. REF 2, Saccone SF, Pergadia ML, Loukola A, Broms U, Montgomery GW, Wang JC, et al. Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples. Am J Hum Genet. 2007; 80(5): REF 3, Haberstick BC, Ehringer MA, Lessem JM, Hopfer CJ, Hewitt JK. Dizziness and the genetic influences on subjective experiences to initial cigarette use. Addiction 2011; 106: REF 4, True WR, Xian H, Scherrer JF, Madden PA, Bucholz KK, Heath AC, et al. Common genetic vulnerability for nicotine and alcohol dependence in men. Arch Gen Psychiatry 1999; 56(7): REF 5, Maes HH, Sullivan PF, Bulik CM, Neale MC, Prescott CA, Eaves LJ, et al. A twin study of genetic and environmental influences on tobacco initiation, regular tobacco use and nicotine dependence. Psychol Med 2004; 34(7): REF 6, Vink JM, Willemsen G, Boomsma DI. Heritability of Smoking Initiation and Nicotine Dependence. Behavior Genetics 2005; 35(4): REF 7, Modig K, Silventoinen K, Tynelius P, Kaprio J, Rasmussen F. Genetics of the association between intelligence and nicotine dependence: a study of male Swedish twins. Addiction 2011; 106(5): REF 8, Lessov CN, Martin NG, Statham DJ, Todorov AA, Slutske WS, Bucholz KK, et al. Defining nicotine dependence for genetic research: evidence from Australian twins. Psychol Med 2004; 34(5): REF 9, Broms U, Madden PA, Heath AC, Pergadia ML, Shiffman S, Kaprio J.The Nicotine Dependence Syndrome Scale in Finnish smokers. Drug Alcohol Depend 2007; 89(1):42-51.

7 Supplemental table 4. A list of 327 SNPs with P <1x10-5 for the studied 17 smoking-related traits. P -values below 1x10-6 are bolded. For each finding, P -values for other smoking related traits showing any association are shown. GWA RESULTS PLEIOTROPIC SIGNALS FROM OTHER SMOKING RELATED TRAITS 1 CPD rs-number chr position MAF P -value location FTND score Maximum CPD TTF rs G 5q x10-6 intron of FSTL CPD rs-number chr position MAF P -value location FTND score NDSS sum score TTF Maximum CPD diagnosis rs G 7p x10-6 intron of CHN CPD rs-number chr position MAF P -value location Maximum CPD NDSS stereotypy/ continuity rs G 12q x kb from CPNE NDSS stereotypy/ Age of onset of CPD rs-number chr position MAF P -value location FTND score TTF Maximum CPD NDSS sum score continuity weekly smoking rs G 13q x kb from SLC10A CPD rs-number chr position MAF P -value location Maximum CPD FTND score TTF NDSS sum score NDSS tolerance rs p x10-6 intron of CLEC19A rs p x10-6 intron of CLEC19A rs p x10-6 intron of CLEC19A rs p x10-6 intron of CLEC19A rs p x10-6 3kb from CLEC19A, 97kb from TMC rs p x10-6 3kb from CLEC19A, 97kb from TMC rs p x10-6 4kb from CLEC19A, 96kb from TMC rs p x10-6 7kb from CLEC19A, 93kb from TMC rs p x10-6 8kb from CLEC19A, 92kb from TMC rs p x10-6 8kb from CLEC19A, 92kb from TMC rs p x10-6 8kb from CLEC19A, 92kb from TMC rs p x10-6 9kb from CLEC19A, 91kb from TMC rs p x10-6 9kb from CLEC19A, 91kb from TMC rs p x10-6 9kb from CLEC19A, 91kb from TMC rs G 16p x10-6 9kb from CLEC19A, 91kb from TMC rs p x10-6 9kb from CLEC19A, 90kb from TMC rs p x10-6 9kb from CLEC19A, 90kb from TMC rs p x kb from CLEC19A, 90kb from TMC rs p x kb from CLEC19A, 74kb from TMC rs p x kb from CLEC19A, 72kb from TMC rs p x kb from CLEC19A, 70kb from TMC rs p x kb from CLEC19A, 70kb from TMC rs G 16p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 68kb from TMC rs p x kb from CLEC19A, 68kb from TMC rs p x kb from CLEC19A, 68kb from TMC rs G 16p x kb from CLEC19A, 66kb from TMC rs p x kb from CLEC19A, 66kb from TMC rs p x kb from CLEC19A, 64kb from TMC rs p x kb from CLEC19A, 63kb from TMC rs p x kb from CLEC19A, 62kb from TMC Maximum CPD rs-number chr position MAF P -value location CPD FTND score TTF NDSS drive/ priority NDSS sum score rs q x kb from NT5E rs q x kb from NT5E Maximum CPD rs-number chr position MAF P -value location CPD FTND score NDSS sum score NDSS tolerance TTF rs q x10-6 2kb from SYNDIG1L rs q x kb from SYNDIG1L rs q x10-6 intron of SYNDIG1L rs G 14q x10-6 intron of SYNDIG1L rs q x10-6 intron of SYNDIG1L rs G 14q x10-6 intron of SYNDIG1L Maximum CPD rs-number chr position MAF P -value location CPD FTND score TTF NDSS sum score NDSS tolerance rs p x kb from CLEC19A, 74kb from TMC rs p x kb from CLEC19A, 70kb from TMC

8 rs p x kb from CLEC19A, 70kb from TMC rs G 16p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 69kb from TMC rs p x kb from CLEC19A, 68kb from TMC rs p x kb from CLEC19A, 68kb from TMC rs p x kb from CLEC19A, 68kb from TMC rs G 16p x kb from CLEC19A, 66kb from TMC rs p x kb from CLEC19A, 66kb from TMC rs p x kb from CLEC19A, 64kb from TMC rs p x kb from CLEC19A, 63kb from TMC rs p x kb from CLEC19A, 62kb from TMC Age at first puff rs-number chr position MAF P -value location Age at first cigarette CPD FTND score rs q x kb from KCNMB rs q x kb from KCNMB rs G 3q x kb from KCNMB rs q x kb from KCNMB rs q x kb from KCNMB Age at first puff rs-number chr position MAF P -value location Age at first cigarette rs p x kb from KIAA1462, 153kb from MTPAP rs p x kb from KIAA1462, 151kb from MTPAP rs p x kb from KIAA1462, 151kb from MTPAP rs p x kb from KIAA1462, 141kb from MTPAP rs p x kb from KIAA1462, 138kb from MTPAP rs p x kb from KIAA1462, 137kb from MTPAP rs p x kb from KIAA1462, 132kb from MTPAP rs G 10p x kb from KIAA1462, 128kb from MTPAP rs p x kb from KIAA1462, 125kb from MTPAP rs p x kb from KIAA1462, 125kb from MTPAP rs G 10p x kb from KIAA1462, 124kb from MTPAP rs G 10p x kb from KIAA1462, 109kb from MTPAP Age at first cigarette Age at first cigarette Age at first cigarette Age of onset of daily Age of onset of rs-number chr position MAF P -value location Age at first puff smoking weekly smoking rs q x kb from UNC5C rs-number chr position MAF P -value location Age of onset of Age of onset of daily Age at first puff weekly smoking smoking rs q x10-6 intron of ST3GAL rs q x10-6 intron of ST3GAL rs G 8q x10-6 intron of ST3GAL rs-number chr position MAF P -value location Age at first puff Maximum CPD Age of onset of Age of onset of daily FTND score weekly smoking smoking CPD TTF NDSS sum score rs p x10-6 intron of NRP rs p x10-6 intron of NRP rs p x10-6 intron of NRP rs G 10p x10-6 intron of NRP Second cigarette rs-number chr position MAF P -value location rs q x kb from LNX1 Second cigarette rs-number chr position MAF P -value location Age at first puff rs G 9p x kb from NFIB Age of onset of weekly smoking Age of onset of weekly smoking Age of onset of weekly smoking Age of onset of daily rs-number chr position MAF P -value location Age at first cigarette Age at first puff smoking rs G 1p x kb from PIGK, 47kb from AK rs p x kb from PIGK, 8kb from AK rs-number chr position MAF P -value location Age of onset of daily Age at first cigarette Age at first puff smoking FTND score rs G 2q x kb from NCKAP5, 431kb from MGAT rs q x kb from NCKAP5, 422kb from MGAT rs q x kb from NCKAP5, 414kb from MGAT rs q x kb from NCKAP5, 411kb from MGAT rs q x kb from NCKAP5, 408kb from MGAT Age of onset of daily rs-number chr position MAF P -value location Age at first cigarette smoking rs p x kb from SMARCA NDSS tolerance

9 Age of onset of weekly smoking Age of onset of daily smoking Age of onset of daily smoking First time sensations First time sensations First time sensations First time sensations First time sensations First time sensations First time sensations Age of onset of daily rs-number chr position MAF P -value location Age at first cigarette smoking rs q x kb from SLC35F Age of onset of NDSS tolerance rs-number chr position MAF P -value location Age at first cigarette Age at first puff FTND score weekly smoking rs G 2q x kb from NCKAP5, 431kb from MGAT Age of onset of rs-number chr position MAF P -value location Age at first cigarette weekly smoking diagnosis rs q x10-6 intron of GRAP rs-number chr position MAF P -value location NDSS tolerance rs G 2q x10-6 intron of THSD7B rs G 2q x10-6 intron of THSD7B rs-number chr position MAF P -value location rs q x kb from FSIP2 rs q x kb from FSIP2 rs q x kb from FSIP2 rs q x kb from FSIP2 rs q x kb from FSIP2 rs q x kb from FSIP2 rs G 2q x kb from FSIP2 rs q x kb from FSIP2 rs q x kb from FSIP2 rs q x kb from FSIP2 rs q x kb from FSIP2 rs q x kb from FSIP2 rs G 2q x10-6 7kb from FSIP2 rs q x10-6 intron of FSIP2 rs q x kb from FSIP2 rs-number chr position MAF P -value location rs G 8p x kb from LOC286114, 393kb from GFRA2 rs p x kb from LOC286114, 392kb from GFRA2 rs p x kb from LOC286114, 392kb from GFRA2 rs G 8p x kb from LOC286114, 392kb from GFRA2 rs p x kb from LOC286114, 388kb from GFRA2 rs p x kb from LOC286114, 384kb from GFRA2 rs p x kb from LOC286114, 376kb from GFRA2 rs p x kb from LOC286114, 375kb from GFRA2 rs p x kb from LOC286114, 369kb from GFRA2 rs p x kb from LOC286114, 359kb from GFRA2 rs p x kb from LOC286114, 354kb from GFRA2 rs p x kb from LOC286114, 351kb from GFRA2 rs p x kb from LOC286114, 350kb from GFRA2 rs G 8p x kb from LOC286114, 350kb from GFRA2 rs p x kb from LOC286114, 347kb from GFRA2 rs p x kb from LOC286114, 347kb from GFRA2 rs-number chr position MAF P -value location rs q x kb from RSPO2 Age of onset of daily rs-number chr position MAF P -value location NDSS sum score smoking rs q x10-6 intron of SLC44A rs-number chr position MAF P -value location rs q x10-6 intron of CORO2B rs q x10-6 intron of CORO2B rs G 15q x10-6 intron of CORO2B rs q x10-6 intron of CORO2B rs-number chr position MAF P -value location Age of onset of weekly smoking rs q x10-6 7kb from KIAA1609, 54kb from COTL1 rs q x kb from KIAA1609, 48kb from COTL rs G 16q x kb from KIAA1609, 48kb from COTL rs q x kb from KIAA1609, 47kb from COTL rs q x kb from KIAA1609, 46kb from COTL

10 diagnosis diagnosis diagnosis diagnosis rs-number chr position MAF P -value location rs p x kb from DCDC2C rs-number chr position MAF P -value location FTND ( 4) rs G 2q x kb from ERBB rs q x kb from ERBB rs q x kb from ERBB rs q x kb from ERBB rs q x kb from ERBB rs q x kb from ERBB rs q x kb from ERBB rs q x kb from ERBB rs q x10-6 3' UTR of ERBB rs q x10-6 3' UTR of ERBB rs q x10-6 3' UTR of ERBB rs G 2q x10-6 3' UTR of ERBB rs q x10-6 3' UTR of ERBB rs G 2q x10-6 intron of ERBB rs q x10-6 intron of ERBB rs q x10-6 intron of ERBB rs q x10-6 intron of ERBB rs-number chr position MAF P -value location FTND ( 4) rs q x10-6 intron of KALRN rs-number chr position MAF P -value location NDSS sum score NDSS drive/ priority NDSS drive/ priority rs G 10q x10-6 intron of ABCC rs q x10-6 intron of ABCC rs G 10q x10-6 intron of ABCC rs-number chr position MAF P -value location TTF FTND score NDSS tolerance rs q x kb from CD28, 95kb from CTLA rs G 2q x kb from CD28, 93kb from CTLA rs q x kb from CD28, 89kb from CTLA rs q x kb from CD28, 86kb from CTLA rs-number chr position MAF P -value location rs G 3p x kb from CADM2 rs-number chr position MAF P -value location FTND score CPD diagnosis TTF Maximum CPD rs p x10-6 intron of TMEM rs p x10-6 intron of TMEM rs-number chr position MAF P -value location Maximum CPD CPD rs q x10-6 no genes within 200kb NDSS tolerance rs-number chr position MAF P -value location rs G 8q x kb from STMN2 rs q x kb from STMN rs-number chr position MAF P -value location FTND score TTF Maximum CPD NDSS drive/ priority rs G 11q x10-6 intron of NTM rs q x10-6 intron of NTM rs q x10-6 intron of NTM CPD FTND ( 4) rs-number chr position MAF P -value location NDSS sum score NDSS drive/ priority Age of onset of daily First time smoking sensations rs q x10-6 intron of CMKLR rs q x10-6 intron of CMKLR rs q x10-6 intron of CMKLR FTND ( 4) rs-number chr position MAF P -value location rs G 15q x kb from LOC91948 FTND score rs-number chr position MAF P -value location TTF CPD Maximum CPD NDSS sum score NDSS stereotypy/ continuity Age at first puff rs q x10-6 intron of GTPBP rs q x10-6 intron of GTPBP

11 rs q x10-6 intron of GTPBP rs q x10-6 intron of GTPBP rs q x10-6 intron of GTPBP FTND score rs-number chr position MAF P -value location TTF NDSS sum score NDSS stereotypy/ continuity FTND ( 4) rs p x10-6 intron of BNC rs G 9p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs G 9p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs G 9p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs p x10-6 intron of BNC rs G 9p x10-6 intron of BNC FTND score rs-number chr position MAF P -value location TTF NDSS sum score NDSS tolerance NDSS stereotypy/ FTND ( 4) continuity diagnosis rs q x kb from LOC rs q x kb from LOC FTND score rs-number chr position MAF P -value location Maximum CPD TTF CPD NDSS sum score rs q x10-6 intron of GLCE rs q x10-6 intron of GLCE rs q x10-6 intron of GLCE rs q x10-6 5kb from GLCE FTND score rs-number chr position MAF P -value location TTF NDSS stereotypy/ continuity rs q x kb from PIK3C3, 382kb from RIT

12 rs q x kb from PIK3C3, 382kb from RIT rs G 18q x kb from PIK3C3, 381kb from RIT rs G 18q x kb from PIK3C3, 380kb from RIT FTND score rs-number chr position MAF P -value location CPD Maximum CPD TTF NDSS drive/priority Age at first cigarette NDSS sum score rs G 18q x kb from LOC rs G 18q x kb from LOC NDSS tolerance FTND score rs-number chr position MAF P -value location CPD TTF Maximum CPD rs G 19q x10-6 5kb from KLK6, 2kb from KLK TTF rs-number chr position MAF P -value location FTND score NDSS sum score CPD rs G 6p x kb from TFAP2A, 165kb from OFCC TTF rs-number chr position MAF P -value location FTND ( 4) FTND score rs G 7q x10-6 intron of ADAM TTF rs-number chr position MAF P -value location NDSS stereotypy/ continuity FTND score NDSS sum score rs q x10-6 intron of PRKG TTF rs-number chr position MAF P -value location FTND score CPD rs q x10-6 intron of POLE Age of onset of daily Age of onset of TTF rs-number chr position MAF P -value location FTND score CPD Age at first cigarette smoking weekly smoking rs q x10-6 intron of ZNF TTF rs-number chr position MAF P -value location FTND score NDSS sum score NDSS stereotypy/ continuity NDSS tolerance rs G 13q x10-6 8kb from FLJ rs q x10-6 intron of FLJ TTF rs-number chr position MAF P -value location FTND score NDSS stereotypy/ continuity rs q x kb from DAAM TTF rs-number chr position MAF P -value location NDSS sum score NDSS drive /priority NDSS stereotypy/ NDSS tolerance FTND score continuity rs q x kb from LACTB, 61kb from TPM rs G 15q x kb from LACTB, 62kb from TPM rs q x kb from LACTB, 63kb from TPM rs G 15q x10-7 9kb from LACTB, 71kb from TPM NDSS stereotypy/ TTF rs-number chr position MAF P -value location FTND score NDSS sum score Maximum CPD continuity rs G 15q x10-6 missense mutation in ACAN (Ile1765Val) TTF rs-number chr position MAF P -value location FTND score CPD rs G 19p x10-6 intron of UNC13A CPD FTND ( 4) First time sensations NDSS drive /priority NDSS drive /priority NDSS drive /priority rs-number chr position MAF P -value location TTF NDSS sum score FTND score Maximum CPD rs q x kb from C4orf rs q x kb from C4orf rs q x kb from C4orf rs q x kb from C4orf rs q x kb from C4orf rs-number chr position MAF P -value location NDSS sum score Age at first puff diagnosis FTND score rs G 10p x kb from ANKRD16, 31kb from GDI rs G 10p x kb from ANKRD16, 31kb from GDI rs p x kb from ANKRD16, 33kb from GDI rs G 10p x kb from ANKRD16, 38kb from GDI rs G 10p x10-6 5kb from ANKRD16, 43kb from GDI rs-number chr position MAF P -value location NDSS sum score First time sensations rs G 10p x10-7 intron of PARD rs p x10-6 intron of PARD rs p x10-6 intron of PARD rs p x10-6 intron of PARD rs p x10-6 intron of PARD Age at first cigarette

13 NDSS drive /priority NDSS drive /priority NDSS drive /priority NDSS drive /priority NDSS stereotypy/ continuity NDSS stereotypy/ continuity NDSS tolerance NDSS tolerance NDSS tolerance NDSS tolerance NDSS tolerance rs-number chr position MAF P -value location NDSS sum score FTND score CPD rs G 14q x10-6 intron of STXBP rs-number chr position MAF P -value location NDSS sum score Maximum CPD NDSS tolerance rs G 14q x10-6 6kb from LOC , 24kb from C14orf rs-number chr position MAF P -value location NDSS sum score Maximum CPD FTND score CPD NDSS tolerance rs G 15q x10-6 intron of UNC13C rs G 15q x10-6 intron of UNC13C rs q x10-6 intron of UNC13C rs q x10-6 intron of UNC13C rs q x10-6 intron of UNC13C rs-number chr position MAF P -value location NDSS sum score TTF rs G 17p x10-6 intron of ABR rs-number chr position MAF P -value location NDSS sum score FTND ( 4) rs p x10-6 intron of DGKB rs p x10-6 intron of DGKB rs-number chr position MAF P -value location NDSS sum score FTND score Maximum CPD TTF CPD FTND ( 4) rs p x kb from LOC , 78kb from C18orf NDSS drive/ priority rs-number chr position MAF P -value location NDSS sum score FTND score TTF rs q x10-6 4kb from SAR1AP rs-number chr position MAF P -value location NDSS sum score TTF FTND score rs q x10-6 4kb from POLD2D rs G 5q x kb from POLD2D rs q x kb from POLD2D rs q x kb from POLD2D rs G 5q x kb from POLD2D rs-number chr position MAF P -value location NDSS sum score rs q x kb from NAMPT, 177kb from FLJ rs q x kb from NAMPT, 175kb from FLJ rs G 7q x kb from NAMPT, 169kb from FLJ rs-number chr position MAF P -value location NDSS sum score rs p x10-6 intron of ANO rs G 12p x10-6 intron of ANO2 rs p x10-6 intron of ANO2 rs p x10-6 intron of ANO2 rs p x10-6 intron of ANO rs p x10-6 intron of ANO2 rs G 12p x10-6 intron of ANO2 rs p x10-6 intron of ANO2 rs p x10-6 intron of ANO rs p x10-6 intron of ANO rs-number chr position MAF P -value location NDSS sum score FTND score NDSS drive/ priority rs q x kb from TTC FTND ( 4) NDSS drive/ priority NDSS stereotypy/ NDSS tolerance NDSS sum score rs-number chr position MAF P -value location continuity rs p x10-6 intron of JAK NDSS drive/ priority Age of onset of NDSS tolerance NDSS stereotypy/ NDSS sum score rs-number chr position MAF P -value location FTND score CPD Maximum CPD TTF Age at first cigarette weekly smoking continuity rs p x10-6 intron of RNF144A NDSS stereotypy/ NDSS drive/ priority NDSS tolerance NDSS sum score rs-number chr position MAF P -value location FTND score TTF Second cigarette continuity rs G 2q x10-6 intron of CNTNAP NDSS drive/ priority NDSS tolerance NDSS sum score rs-number chr position MAF P -value location Maximum CPD rs G 14q x10-6 6kb from LOC , 24kb from C14orf

14 NDSS drive/ priority NDSS tolerance NDSS sum score rs-number chr position MAF P -value location Maximum CPD FTND score CPD FTND ( 4) rs q x10-6 intron of UNC13C rs G 15q x10-6 intron of UNC13C rs G 15q x10-6 intron of UNC13C NDSS sum score rs-number chr position MAF P -value location NDSS tolerance NDSS drive/ priority NDSS stereotypy/ continuity Maximum CPD FTND score rs q x10-6 3' UTR of EMID1, 428bp from RHBDD3 3' rs q x10-6 synonymous change in RHBDD3 (Glu132Glu) rs G 22q x10-6 intron of RHBDD NDSS tolerance NDSS drive/ priority NDSS stereotypy/ NDSS sum score rs-number chr position MAF P -value location FTND score Maximum CPD continuity rs q x10-6 intron of EWSR , Trait definitions are presented in Supplemental table 1. P -values in the magnitude of 10-2 are highlighted in yellow; P -values in the magnitude of 10-3 are highlighted in orange; P -values in the magnitude of 10-4 are highlighted in red. 2, CPNE3 highlighted in a previous meta analysis (Tobacco and Genetics Consortium. Nat Genet 2010; 42: ). LD, linkage disequilibrium; position, base pair position according to NCBI36/hg18; MAF, minor allele frequency; G, genotyped (all others imputed, reference panel HapMap rel#24 CEU - NCBI Build 36 (dbsnp b126))

15 Supplemental table 5. List of 55 genes with at least one SNP with P <1x10-5 within ±50kb flanking of the gene. A total of 33 genes for which the involvement in smoking-related traits is supported by convergent data are bolded. Chr Gene Trait 1 SNPs 2 Genebased Replication 4 Pleiotropic signals (P 10-4 ) 5 Gene highlighted in a P - previous smoking related value 3 GWA study 6 1p31.1 AK5 Age of onset of weekly smoking 375 / 2 / x10-3 Age of onset of daily smoking (0.87), Age at first cigarette (0.71) Gene highlighted in a previous GWA study of use/dependence on other substances 7 Substance use GWA (Johnson et al. BMC Med Genet. 2008; 9: ), illicit drug dependence GWA (Drgon et al. Am J Med Genet B Neuropsychiatr Genet. 2011; 156(2): ), metamphetamine dependence GWA (Uhl et al. Arch Gen Psychiatry. 2008; 65(3): ) Location in smoking behavior/nd linkage locus identified in the same Finnish sample 8 or in a metaanalysis 9 Relevant known / suspected function 11 1p31.1 PIGK Age of onset of weekly smoking 190 / 1 / x10-3 Age of onset of daily smoking (0.87), Age at first cigarette (0.71) 1p31.3 JAK1 NDSS sum score 172 / 1 / x10-4 NDSS drive/priority (0.69) 2p25.2-p25.1 RNF144A NDSS sum score 282 / 1 / x10-4 FTND score (0.62), CPD (0.48) Smoking cessation (Uhl et al. Pharmacogenomics 2010; 11: ) 2q14.3 CNTNAP5 NDSS sum score 916 / 1 / x10-3 Meta-analysis: Max CPD locus on 2q12.3-q22.3. Belongs to the neurexin family, members of which function in the vertebrate nervous system as cell adhesion molecules and receptors. 2q22.1 THSD7B First time sensations 689 / 2 / x10-4 Alcohol dependence GWA (Wang et a. J Psychiatr Res. 2011; 45(11): ). Meta-analysis: Max CPD locus on 2q12.3-q q32.1 FSIP2 First time sensations 105 / 5 / x10-5 Alcohol withdrawal GWA (Wang et al. J Neural Transm. 2012; 199: ) 2q33.2 CD28 72 / 4 / x10-5 Finnish sample: 2q33 smoker locus. 2q33.3-q34 ERBB4 diagnosis 1349 / 17 / x10-3 Association with DSM-IV ND in the NAG-OZALC sample (P =10-4 ). (0.93) Alcohol dependence GWA (Kendler et al. Alcohol Clin Exp Res. 2011; 35(5): ) Finnish sample: 2q33 smoker locus. Meta-analysis: Max CPD locus on 2q34- q37.1. Belongs to the tyrosine protein kinase family and the epidermal growth receptor subfamily, acts as cell-surface receptor for the neuregulins (NRG1, NRG2, NRG3, and NRG4). 3q21.1 KALRN diagnosis 679 / 1 / x10-3 Protein kinase, involved in e.g. nerve growth receptor signaling pathway and nervous system development. 4p14 TMEM / 2 / x10-4 Meta-analysis: FTND locus on 4p p12. 4q12 LNX1 Second cigarette 233 / 1 / x10-3 Smoking cessation (Uhl et al. Mol Med 2010; 16: ) 4q27 SAR1AP3 NDSS tolerance 91 / 1 / x10-4 5q15 POLD2D1 NDSS tolerance 50 / 5 / x10-5 NDSS sum score (0.60) Meta-analysis: Smoking behavior and FTND locus on 5q14.1-q q31.1 FSTL4 CPD 473 / 1 / x10-2 7p15.1 CHN2 CPD 578 / 1 / x10-3 FTND score (0.71) Smoking cessation (Uhl et al. Arch Gen Psychiatry 2008; 65: ) 7p21.2 DGKB NDSS stereotypy/continuity 887 / 2 / x10-4 Smoking cessation (Uhl et al. Mol Med 2010; 16: ) Alcohol dependence GWA (Kendler et al. Alcohol Clin Exp Res. 2011; 35(5): ) Direct interaction between ErbB2 and LNX1 (Young et al. Mol Cell Neurosci. 2005; 30(2): ) Member of the chimerin family, plays a role in the proliferation and migration of smooth muscle cells, mutations associated with schizophrenia in men. 7q21.12 ADAM22 TTF 146 / 1 / x10-2 Finnish sample: 7q21-q31 FTND locus. Belongs to the ADAM (a disintegrin and metalloprotease domain) family, members of which have been implicated in neurogenesis. 7q21.13 GTPBP10 FTND score 243 / 5 / x10-5 TTF (0.84), CPD (0.71) Finnish sample: 7q21-q31 FTND locus. 8q24.22 ST3GAL1 Age at first cigarette 263 / 3 / x10-5 Age of onset of weekly smoking (0.71), Age of onset of daily smoking (0.63), Age at first puff (0.77) Smoking cessation (Uhl et al. Mol Med 2010; 16: ; Uhl et al. Arch Gen Psychiatry 2008; 65: ) 9p22.3-p22.2 BNC2 FTND score 641 / 54 / x10-5 TTF (0.84) Smoking cessation (Uhl et al. Arch Gen Psychiatry 2008; 65: ) 9q31.1 SLC44A1 First time sensations 206 / 1 / x p11.21 PARD3 NDSS drive/priority 612 / 4 / x10-4 NDSS sum score (0.69) Smoking cessation (Uhl et al. Arch Gen Psychiatry 2008; 65: ) 10p11.22 NRP1 Age at first cigarette 350 / 4 / x10-5 Age at first puff (0.77), max CPD (- 0.33) 10p15.1 ANKRD16 NDSS drive/priority 142 / 5 / x10-5 NDSS sum score (0.69) Substance use GWA (Johnson et al. BMC Med Genet. 2008; 9: ) 10p15.1 GDI2 NDSS drive/priority 95 / 5 / x10-5 NDSS sum score (0.69) Adapter protein involved in asymmetrical cell division and cell polarization processes, required for neuronal polarity and normal axon formation in cultured hippocampal neurons. A membrane-bound coreceptor to a tyrosine kinase receptor, role in neural development (axon guidance).