This study carried out an across-sample transcriptome-neuroimaging spatial association analysis between the FER-related brain activation and gene expressions in the human brain. A total of 153 genes were identified to associate with FER-related brain activation. Enrichment analyses showed that these FER-related genes are mainly overexpressed in the brain, especially in the neurons, and closely related to the cell junction, neuron development, and synaptic function. Diseases enrichment analyses confirmed that these genes were associated with psychiatric diseases with emotion impairments.
Consistent with previous works using the HCP dataset (Barch et al., 2013; Hariri, Tessitore, et al., 2002), we found that the FER task could robustly activate the emotion-related brain regions such as the amygdala in all ten groups. Moreover, the activation pattern was also consistent with many previous studies on the expression recognition tasks (Fusar-Poli et al., 2009; Phan et al., 2002; Vytal & Hamann, 2010). These results demonstrated that emotion task in the HCP could stimulate reliable FER-related brain activation.
Although candidate gene studies and GWAS revealed some genetic loci associated with emotion, the studies usually provide limited insight into the transcriptional mechanism of emotion. An alternate method is the across-sample transcriptome-neuroimaging spatial association analysis which was widely used to investigate transcriptional mechanisms of cognitive activities and psychiatric disorders (Forest et al., 2017; Ritchie et al., 2018; Xie et al., 2020). It has been demonstrated that this method could reliably link neuroimaging maps from living brains with gene expression from postmortem brains (Berto, Wang, Germi, Lega, & Konopka, 2018; Forest et al., 2017; M. Hawrylycz et al., 2015).
To increase the reliability of the results, we randomly divided the 203 subjects into two groups, and this step was repeated five times. Finally, 153 genes that exhibited association with FER-related brain activation in the same direction in all ten groups were defined as the FER-related genes. We further compared the FER-related genes with the other cognitive task-related genes to evaluate whether 153 genes were specific to the FER. Our results indicated that FER-related genes were partly different from the other cognitive task-related genes, and FER shared some genes with working memory (48 genes), language (69 genes), and social cognition (40 genes). These results suggested that FER might have some specific regulatory genes and might be also modulated by some genes related to other cognitive functions. This explanation was supported by the previous studies that showed emotion had shared some similar neuroanatomical and neurophysiological basis with language, social cognition, and working memory. For instance, a research demonstrated a strong positive correlation between emotional competence and language competence in children (Beck, Kumschick, Eid, & Klann-Delius, 2012). Emotion shared bilateral prefrontal function with working memory in an fMRI study (Mitchell, 2007). Robust correlations were found between social cognition skills and facial processing (Petroni et al., 2011). Enrichment analyses revealed that FER-related genes are mainly overexpressed in the brain, especially neurons. GO enrichment showed that FER-related genes were mainly associated with anterograde trans-synaptic signaling, cell junction organization, chemical synaptic transmission, and neurodevelopment including neuron projection development, neuron development, and nervous system development. And a couple of cellular components including synapse, distal axon, and neuron projection showed significant association. Those findings highlighted the importance of the genes modulating the synaptic functions, neuronal structures, and development in FER processing. For example, MET in the term nervous system development, which encodes Met Receptor Tyrosine Kinase, was known to affect facial expression perception (Lin et al., 2012) and could increase the risk for ASD (Abrahams et al., 2013; Campbell et al., 2007; Campbell et al., 2006; Jackson et al., 2009). CTNNB1 in the term neuron development, which encodes catenin beta 1, is associated with fear-memory consolidation, ASD, and anxiety-related behavior (Dong et al., 2016; Maguschak & Ressler, 2008; Wang et al., 2017). SHANK2 (H3- and multiple ankyrin repeats protein 2), a gene involved in ASD (Bavamian et al., 2015), is related to cell junction organization and chemical synaptic transmission. A PPI network was constructed using 153 FER-related genes. The top five most connecting key genes were identified, including NRXN2, CHRNA4, NLGN1, ACHE, and FYN. Those genes may play an important role in emotion recognition. For instance, CHRNA4, which encodes cholinergic receptor nicotinic alpha 4 subunit, is associated with negative emotion (Markett, Montag, & Reuter, 2011), ADHD (Lasky-Su et al., 2008), and depression (Tsai et al., 2012). A previous GWAS study showed that rs1044396 polymorphism in CHRNA4 is related to several conceptualizations of negative emotionality. NRXN2 encoding neurexin 2, a kind of neuronal adhesion protein, is important in neurotransmitter secretion and synaptic cell adhesion (Missler et al.) and is associated with ASD and SCZ (Gauthier et al., 2011; Mohrmann, Gillessen-Kaesbach, Siebert, Caliebe, & Hellenbroich, 2011; Tromp, Mowry, & Giacomotto, 2021). Previous studies suggested that NLGN1, encoding neuroligin 1, was associated with many psychiatric disorders related to emotion such as PTSD, MDD, ASD, SCZ (Feng, Akladious, & Hu, 2016; Glessner et al., 2009; Kilaru et al., 2016; Lewis et al., 2010; Schizophrenia Working Group of the Psychiatric Genomics, 2014; Sudhof, 2008; Yue et al., 2011). FYN is a member of the Src family of nonreceptor-type tyrosine kinase and is essential for fear memory and anxiety (Isosaka et al., 2008; Skelton et al., 2003). For example, fear memory was impaired in FYN-deficient mice (Isosaka et al., 2008). Previous work indicated that stress-induced alternative splicing of the ACHE gene was important for contextual fear and synaptic plasticity (Nijholt et al., 2004). Enrichment analysis of the PPI network indicated that the FER-related genes were mainly overexpressed in cell junction, nervous system development, and synapse, consistent with the GO enrichment results.
FER deficits have been observed in individuals with ASD (Harms et al., 2010), SCZ (Kohler, Walker, Martin, Healey, & Moberg, 2010; Kring & Elis, 2013), BP (Kohler et al., 2011), and MDD (Bourke et al., 2010; Demenescu, Kortekaas, den Boer, & Aleman, 2010). In this study, the FER-related genes showed significant enrichment for the psychiatric conditions with heavy emotion impairments such as ADHD, ASD, SCZ, BP, and MDD. However, AD showed no significance. These results suggested that FER-related genes were associated with psychiatric diseases, which might help understand the mechanism of the FER impairments in these psychiatric disorders.
Several limitations should be mentioned in this study. First, transcriptome data was extracted from the left cerebral hemispheres of six postmortem adult brains in AHBA. The small sample size might bias our findings. Second, gene expression data and FER-related brain activation data were derived from the different subjects. Although gene expression patterns were confirmed to be conserved across individuals (M. Hawrylycz et al., 2015; Zeng et al., 2012), this influence could not be completely ruled out. To reduce this impact, we randomly divided neuroimaging data into two groups and repeated it five times. Only genes that exhibited consistently significant associations in the same direction in ten groups were defined as FER-related genes. Finally, causal effects between gene expression and FER-related brain activation could not be clarified by this transcription-neuroimaging association analysis.