MA AND SERT EFFECTS ON AGGRESSION AND BRAIN Supplementary Materials 1
In the case of the two SERT polymorphisms investigated here, the role of epistasis is unclear, and their combination therefore potentially problematic. The functional interactions between the two polymorphisms are unknown, and it could be the case that the end phenotype reported in the manuscript is not predicted from the effects of the two variants in isolation. For this reason, we present here the effects of the LPR and STin2 polymorphisms separately, and show that the patterns reported in the manuscript hold true for each polymorphism considered alone (but are only significant in combination).
SERT-LPR:
The sample who had completed the Aggression Questionnaire (AQ) consisted of 36 healthy control (HC) (s+ n = 26, s- n = 10) and 38 MA-dependent participants (s+ n = 25, s- n =
13). S+ denotes short allele carriers (s/l and s/s) and s- denotes long allele homozygotes.
ANOVA of AQ scores, with MA abuse status (MA or HC) and LPR genotype (collapsed according to criteria in the manuscript) as factors, showed identical patterns to those reported in the manuscript, with a main effect of MA abuse status, F(1,70) = 9.03, p = .004, and main effect of genotype, F(1,70) = 4.66, p =
.034, but no interaction, F(1,70) < 1, p = .857 (Supplementary Figure 1A). Even when considering the three possible allele combinations separately (i.e., not collapsing across s+ individuals; s/s n = 7 HC, 10
MA; s/l n = 19 HC, 15 MA), the findings remained identical, with a main effect of MA abuse status,
F(1,68) = 8.36, p = .005, a main effect of genotype, F(2,68) = 6.10, p = .004, and no interaction, F(2,68) <
1, p = .934 (Supplementary Figure 1B).
Figure 1

MA AND SERT EFFECTS ON AGGRESSION AND BRAIN Supplementary Materials 2
The sample who had undergone MRI consisted of 23 HC (s+ n = 18, s- n = 5) and 24 MA (s+ n =
17, s- n = 7). Although mean amygdala activation values (percent signal change during observation of faces) showed the same patterns reported in the manuscript (lower amygdala activation in “high genetic risk” (s+) than “low genetic risk” (s-) individuals), ANOVA of these values showed no significant effects of MA abuse status, F(1,43) = 1.70, p = .200, genotype, F(1,43) = 1.47, p = .231, or interaction, F(1,43) <
1, p = .660. When considering the three allele combinations separately (s/s n = 6 HC, 7 MA; s/l n = 12
HC, 10 MA), the ANOVA showed a main effect of genotype, F(2,41) = 7.70, p = .001, but no effect of
MA abuse status, F(1,41) = 1.14, p = .293, or interaction, F(2,41) < 1, p = .577 (Supplementary Figures 2
A and B), echoing the findings reported in the manuscript.
Figure 2
STin2 VNTR:
The sample who had completed the AQ consisted of 36 HC (10+ n = 17, 10- n = 19) and
35 MA (10+ n = 21, 10- n = 14). 10+ denotes 10-repeat allele carriers (10/10 and 10/12), 10- denotes 12-repeat allele homozygotes. ANOVA of AQ scores, with MA abuse status and STin2 genotype (collapsed according to criteria in the paper) as factors, showed an effect of MA abuse status,
F(1,67) = 9.17, p = .003, but although mean values showed the same pattern as that reported in the manuscript (higher AQ scores in “high genetic risk” (10-) than “low genetic risk” (10+)

MA AND SERT EFFECTS ON AGGRESSION AND BRAIN Supplementary Materials 3 participants, no significant effect of genotype, F(1,67) < 1, p = .639, or interaction, F(1,67) < 1, p
= .363. C onsidering the three allele combinations separately (10/10 n = 3 HC, 7 MA; 10/12 = 14
HC, 14 MA) led to identical results (Supplementary Figures 3 A and B).
Figure 3
The sample who had undergone MRI consisted of 23 HC (10+ n = 11, 10- n = 12,) and 22
MA (10+ n = 14, 10- n = 8,). ANOVA of amygdala activation (percent signal change) showed a marginal effect of genotype, F(1,41) = 3.94, p = .054, but no effect of MA abuse status, F(1,41)
= 1.74, p = .195, or interaction, F(1,41) < 1, p = .758, echoing results reported in the manuscript
(lower amygdala activation in “high genetic risk” than “low genetic risk” participants). When considering genotypes separately (10/10 n = 1 HC, 4 MA; 10/12 n = 10 HC, 10 MA), mean values once again showed patterns identical to those reported in the manuscript, but the ANOVA showed only marginal effects of genotype, F(2,39) = 2.82, p = .072 and MA abuse status, F(1,39)
= 2.82, p = .101, and no interaction, F(2,39) < 1, p = .591 (Supplementary Figures 4 A and B).
Figure 4

MA AND SERT EFFECTS ON AGGRESSION AND BRAIN Supplementary Materials 4
In summary, effects of the polymorphisms of interest considered separately recapitulate those reported in the manuscript, but at non-significant or trend levels. Only in combination (as reported in the main manuscript) were the effects robust.