Online supplement (references)
i) 5-HTT x SLE on depression
An interaction reported between stressful life events (SLEs) and variation within a
polymorphism in the serotonin transporter gene (5-HTTLPR) on risk of depression received
substantial media attention, and has undoubtedly been influential in the large increase in
studies examining GxE over recent years. In the original report (1), presence of SLEs was
associated with increased risk of depression in subjects homozygous for the s-allele (OR for
depression per SLE = 1.68, 95% CI 1.23, 2.30), with a weaker effect in heterozygotes (OR =
1.48, 95% CI 1.24, 1.76), and especially l-allele homozygotes (OR = 1.17, 95% CI 0.91, 1.51).
Risk of depression when exposed to both SLEs and 5HTT s-allele was greater than
multiplicative (and hence also greater than additive).
Of 33 studies that have examined this relationship since then, 17 have examined whether
this relationship is indeed greater than multiplicative. Of these, only 2 find a pattern of
interaction consistent with that in the originally study (2, 3) (1 of these in a sub-group only
(2)), 8 find evidence of interaction but with patterns inconsistent with that originally
reported (4-11) (4 of these in the opposite direction (5, 6, 8, 11)), and 7 fail to find evidence
of any interaction (5, 12-17) (5 of these with sample sizes substantially larger than the
original (5, 12, 13, 15, 17)).
Of 15 studies that examined additive models, 6 reported interactions with patterns
consistent with the original study (18-23) (2 in subgroups only (22, 23)), 3 found patterns
that were inconsistent with the original (24-26) (1 in the opposite direction (26)), and 6
failed to find evidence of interaction (27-32), though sample sizes were on average, 3-times
smaller than the original study. Two of these 6 studies reported GxE in subsequent subgroup
analyses (27, 28).
ii) MAOA x maltreatment on antisocial or violent behaviour
An interaction between variation in the monoamine oxidase A gene (MAOA) and childhood
maltreatment on antisocial and violent behaviour in males was reported (33), such that the
effect of maltreatment was greater with the low activity variants of MAOA compared to
those with high activity. Again, this relationship was greater than multiplicative.
Of 11 studies that have since examined this in males, only 4 have examined whether this
relationship was indeed greater than multiplicative (34-37). Of these, 3 found no evidence
for such a relationship (35-37), whilst 1 found support present only when reporting a 1-tailed
p value (34). Of 10 studies that examined additive models, 5 reported evidence of a greater
than additive effect (38-42) (2 of these in subgroup analyses only (38, 39)), 4 found no
evidence (35, 36, 43, 44), and 1 found evidence of an interaction but in the opposite
direction to that originally reported (45). In samples that also included females, 1 study
examined a multiplicative relationship and found an interaction in the opposite direction
(46). Of 6 studies that examined additive models, 2 found evidence of a greater than additive
effect (47, 48), 3 failed to do so (38, 39, 49), and 1 found an effect in the opposite direction
(50). Studies finding, or failing to find evidence of interaction were equable in size.
iii) COMT x cannabis on psychosis
An interaction between variation in COMT Val158Met (rs4680) genotype and cannabis on
psychosis was reported (51), such that the effect of cannabis was greater in individuals with
the valine (high activity) variant compared to those with the methionine allele. Again, this
relationship was more than multiplicative, with cannabis use associated with a 10-fold
increase in psychosis risk in valine homozygotes, but with no increase in risk in methionine
homozygotes. If such an interaction effect size was correct, then we would expect main
effects to be observed for both exposures without the need to study interactions given the
frequencies of the valine allele and of cannabis use in the population, but even in large
meta-analyses the association between COMT Val158Met and schizophrenia remains
uncertain (52), despite more than adequately-sized samples to identify a main effect if an
interaction with cannabis existed as described above. Three studies that have subsequently
examined this relationship (see online supplement) found no evidence to support a
relationship as originally reported (53-55). In one of these studies an interaction was
reported but only from a subgroup (and 3-way interaction) analysis (53).
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