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Replication and heterogeneity in gene×environment interaction studies

Marcus R. Munafò, Jonathan Flint
DOI: http://dx.doi.org/10.1017/S1461145709000479 727-729 First published online: 1 July 2009

There has been considerable interest in gene×environment (G×E) interactions in psychiatric genetics since studies by Caspi and colleagues (Caspi et al. 2002, 2003) suggested that these may illuminate the aetiology and genetic architecture of behavioural phenotypes. However, as with earlier candidate gene studies (Ioannidis et al. 2001), initial promise was subsequently followed by failures to replicate and increasing inconsistency in the rapidly growing G×E literature (Munafò et al. 2009a). One reason for this is that the greater number of potential statistical tests that are possible when interaction effects are included in any analysis (e.g. by investigating multiple markers of environmental exposures) greatly increases the risk of false positives in studies of this kind (Munafò et al. 2009a). However, another possibility is that there is genuine heterogeneity between studies, which reflects the sampling of different populations across which the genetic effects of interest may vary in strength or direction.

Laucht and colleagues (Laucht et al. 2009) report evidence that individuals homozygous for the L allele of the 5-HTTLPR displayed higher rates of depressive or anxiety disorders when exposed to environmental adversity, contrary to the original report by Caspi and colleagues in which possession of the S allele increased susceptibility to depression under stressful conditions (Caspi et al. 2003). Laucht and colleagues argue that a ‘possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity’. An alternative and perhaps more parsimonious explanation is that their result is further evidence that the literature to date is compatible with chance findings, perhaps …

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