Human brain arousal in the resting state: a genome-wide association study.
Philippe JawinskiHolger KirstenChristian SandersJanek SpadaChristine UlkeJue HuangRalph BurkhardtMarkus ScholzTilman HenschUlrich HegerlPublished in: Molecular psychiatry (2018)
Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p < 5E-8), although seven loci were suggestive (p < 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer's Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.
Keyphrases
- resting state
- genome wide association study
- genome wide
- functional connectivity
- major depressive disorder
- copy number
- dna methylation
- autism spectrum disorder
- bipolar disorder
- poor prognosis
- single cell
- high resolution
- machine learning
- mild cognitive impairment
- small molecule
- intellectual disability
- gene expression
- attention deficit hyperactivity disorder
- cognitive decline
- mental health
- emergency department
- sleep quality
- white matter
- deep learning
- blood brain barrier
- climate change
- adverse drug
- single molecule
- risk assessment
- transcription factor
- human health
- cerebral ischemia
- genome wide identification