Replication in Imaging Genetics: The Case of Threat-Related Amygdala Reactivity

Abstract

Background: Low replication rates are a concern in most, if not all, scientific disciplines. In psychiatric genetics specifically, targeting intermediate brain phenotypes, which are more closely associated with putative genetic effects, was touted as a strategy leading to increased power and replicability. In the current study, we attempted to replicate previously published associations between single nucleotide polymorphisms and threat-related amygdala reactivity, which represents a robust brain phenotype not only implicated in the pathophysiology of multiple disorders, but also used as a biomarker of future risk.

Methods: We conducted a literature search for published associations between single nucleotide polymorphisms and threat-related amygdala reactivity and found 37 unique findings. Our replication sample consisted of 1117 young adult volunteers (629 women, mean age 19.72 ± 1.25 years) for whom both genetic and functional magnetic resonance imaging data were available.

Results: Of the 37 unique associations identified, only three replicated as previously reported. When exploratory analyses were conducted with different model parameters compared to the original findings, significant associations were identified for 28 additional studies: eight of these were for a different contrast/laterality; five for a different gender and/or race/ethnicity; and 15 in the opposite direction and for a different contrast, laterality, gender, and/or race/ethnicity. No significant associations, regardless of model parameters, were detected for six studies. Notably, none of the significant associations survived correction for multiple comparisons.

Conclusions: We discuss these patterns of poor replication with regard to the general strategy of targeting intermediate brain phenotypes in genetic association studies and the growing importance of advancing the replicability of imaging genetics findings.

Keywords: Amygdala; Functional MRI; Genes; Imaging genetics; Replication; Single nucleotide polymorphism.

Figure 1

Reproducibility in imaging genetics of threat-related amygdala reactivity. Note. Yes - full replication; Different contrast or laterality - partial replication. Significant with a change in fMRI task contrast and/or hemispheric laterality; Different population: association was significant in a different gender and/or ethnicity; No - was not replicated in any tested model ; and opposite direction - the allele/genotype that was previously associated with higher reactivity was associated with lower reactivity in our sample (most of these associations also differed in contrast, laterality, and/or ethnicity).