Dataset Information

Heritability of amygdala reactivity to angry faces and its replicable association with the schizophrenia risk locus of miR-137.

ABSTRACT:

Background

Among healthy participants, the interindividual variability of brain response to facial emotions is associated with genetic variation, including common risk variants for schizophrenia, a heritable brain disorder characterized by anomalies in emotion processing. We aimed to identify genetic variants associated with heritable brain activity during processing of facial emotions among healthy participants and to explore the impact of these identified variants among patients with schizophrenia.

Methods

We conducted a data-driven stepwise study including samples of healthy twins, unrelated healthy participants and patients with schizophrenia. Participants approached or avoided pictures of faces with negative emotional valence during functional magnetic resonance imaging (fMRI).

Results

We investigated 3 samples of healthy participants - including 28 healthy twin pairs, 289 unrelated healthy participants (genome-wide association study [GWAS] discovery sample) and 90 unrelated healthy participants (replication sample) - and 1 sample of 48 patients with schizophrenia. Among healthy twins, we identified the amygdala as the brain region with the highest heritability during processing of angry faces (heritability estimate 0.54, p < 0.001). Subsequent GWAS in both discovery and replication samples of healthy non-twins indicated that amygdala activity was associated with a polymorphism in the miR-137 locus (rs1198575), a micro-RNA strongly involved in risk for schizophrenia. A significant effect in the same direction was found among patients with schizophrenia (p = 0.03).

Limitations

The limited sample size available for GWAS analyses may require further replication of results.

Conclusion

Our data-driven approach shows preliminary evidence that amygdala activity, as evaluated with our task, is heritable. Our genetic associations preliminarily suggest a role for miR-137 in brain activity during explicit processing of facial emotions among healthy participants and patients with schizophrenia, pointing to the amygdala as a brain region whose activity is related to miR-137.

SUBMITTER: Quarto T

PROVIDER: S-EPMC10521919 | biostudies-literature | 2023 Sep-Oct

REPOSITORIES: biostudies-literature

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Publications

Heritability of amygdala reactivity to angry faces and its replicable association with the schizophrenia risk locus of <i>miR-137</i>.

Quarto Tiziana T Lella Annalisa A Di Carlo Pasquale P Rampino Antonio A Paladini Vittoria V Papalino Marco M Romano Raffaella R Fazio Leonardo L Marvulli Daniela D Popolizio Teresa T Blasi Giuseppe G Pergola Giulio G Bertolino Alessandro A

Journal of psychiatry & neuroscience : JPN 20230926 5

<h4>Background</h4>Among healthy participants, the interindividual variability of brain response to facial emotions is associated with genetic variation, including common risk variants for schizophrenia, a heritable brain disorder characterized by anomalies in emotion processing. We aimed to identify genetic variants associated with heritable brain activity during processing of facial emotions among healthy participants and to explore the impact of these identified variants among patients with s ...[more]

PMID: 37751917

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Project description:Abstract Background It is well known that heritability plays a prominent role in risk for schizophrenia, and that this brain disorder is crucially characterized by emotional symptoms. Less known is how heritability shapes brain activity during emotion processing and whether this brain phenotype is also associated with genetic variation increasing risk for schizophrenia. Here, we implemented a multi-step, data-driven approach in order to assess the relevance of the link between heritability, genetic variation, and schizophrenia for brain activity during emotion processing. Methods We investigated three samples of healthy individuals and one sample of schizophrenia (SCZ) patients: i) 28 healthy twin pairs (16 monozygotic and 12 dizygotic twin pairs); ii) 289 unrelated healthy participants (genome-wide association study - GWAS -discovery sample); iii) 90 unrelated healthy participants (replication sample); iv) 40 SCZ patients. During fMRI, participants approached or avoided threatening angry faces (explicit emotion processing). Intra-class correlations (ICC) between twin pairs and ACE models (A: additive genetics; C: common environment; E: unique environment) were used to identify regions of interest (ROIs) with heritable functional activity. Then, we extracted BOLD signal from these ROIs and conducted a GWAS on 565,137 single nucleotide polymorphisms (SNPs) (selected with the following criteria: minor allele frequency>0.15, Hardy–Weinberg equilibrium<0.001, linkage disequilibrium pruning r2>0.9) using robust linear models of allelic dosage corrected for multiple comparisons (Gao et al. 2008 Genetic Epidemiology). Finally, we assessed the effect of surviving SNPs in the replication sample of healthy individuals as well as in the sample of SCZ patients. Results In healthy twins, we identified bilateral amygdala as the brain region with the highest heritability during explicit emotion processing as evaluated with our task (ICC=.79; h2=0.54; p<.001). The subsequent GWAS in healthy non-twins indicated that bilateral amygdala activity during the task was associated with a polymorphism close to miR-137 (rs1198575) (p=1.5 × 10–7), with the C allele corresponding to lower activity than the t allele. A similar effect was found in the replication sample (p=.01) and in patients with SCZ (p=.03). Discussion Our data-driven approach revealed that amygdala activity as evaluated with our task is heritable. Furthermore, our results indicate that a polymorphism in miR-137 has genome wide association with amygdala response during emotion processing which is also replicated in two independent samples of healthy subjects and of patients with schizophrenia. Previous findings indicated that this polymorphism has genome-wide association with schizophrenia (Ripke et al. 2014). Other results reveal that miR-137 is a key regulatory neuronal factor linked to SCZ and involved in emotion processing (Cosgrove et al., 2017). Our findings are consistent with these previous findings and further highlight a crucial role for miR-137 in emotion processing and SCZ (Anticevic et al., 2012 Schizophr Bull).