The genetic architecture of human brainstem structures and their involvement in common brain disorders

Elvsåshagen, Torbjørn; Bahrami, Shahram; Meer, Dennis van der; Alnæs, Dag; Barch, Deanna M.; Baur‐Streubel, Ramona; Bertolino, Alessandro; Beyer, Mona K.; Blasi, Giuseppe; Borgwardt, Stefan; Boye, Birgitte; Buitelaar, Jan K.; Bøen, Erlend; Celius, Elisabeth Gulowsen; Conzelmann, Annette; Coynel, David; Carlo, Pasquale Di; Djurovic, Srdjan; Eisenacher, Sarah; Espeseth, Thomas; Franke, Barbara; Frei, Oleksandr; Harbo, Hanne F.; Hartman, Catharina A.; Håberg, Asta; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Høgestøl, Einar August; Jonassen, Rune; Jönsson, Erik G.; Farde, Lars; Flyckt, Lena; Engberg, Göran; S, S. Erhardt; Fatouros‐Bergman, Helena; Červenka, Simon; Schwieler, Lilly; Piehl, Fredrik; Agartz, Ingrid; Collste, Karin; Victorsson, P; Malmqvist, Anna; Hedberg, Magnus; Orhan, Funda; Sellgren, Carl M.; Kirsch, Peter; Kłoszewska, Iwona; Lagerberg, Trine Vik; Landrø, Nils Inge; Hellard, Stéphanie Le; Lesch, Klaus‐Peter; Maglanoc, Luigi A.; Malt, Ulrik Fredrik; Mecocci, Patrizia; Melle, Ingrid; Meyer‐Lindenberg, Andreas; Moberget, Torgeir; Nordvik, Jan Egil; Nyberg, Lars; O’Connell, Kevin; Oosterlaan, Jaap; Papalino, Marco; Papassotiropoulos, Andreas; Pauli, Paul; Pergola, Giulio; Persson, Karin; Quervain, Dominique de; Reif, Andreas; Rokicki, Jaroslav; Rooij, Daan van; Shadrin, Alexey; Schmidt, André; Schwarz, Emanuel; Selbæk, Geir; Soininen, Hilkka; Sowa, Piotr; Steen, Vidar M.; Tsolaki, Magda; Vellas, Bruno; Wang, Lei; Westman, Eric; Ziegler, Georg C.; Zink, Mathias; Andreassen, Ole A.; Westlye, Lars T.; Kaufmann, Tobias

doi:10.1038/s41467-020-17376-1

Cited by 31 publications

(30 citation statements)

References 72 publications

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“…We found that the majority of thalamus-linked loci and genes were associated with only one of the seven volumes, which may suggest at least partly independent genetic architectures. This demonstrates the importance of targeting individual nuclei rather than studying the thalamus as a whole, in line with similar benefits observed for other brain structures 19 , 20 . In addition, we found genetic correlations between the thalamic nuclei and distinct cortical regions.…”

Section: Resultssupporting

confidence: 73%

“…We conducted GWAS with PLINK 18 on whole thalamus and the six nuclei volumes accounting for age, age-orthogonalized age-squared, sex, scanning site, intracranial volume, and the first 20 genetic principal components. The thalamic nuclei GWAS also accounted for whole thalamus volume, thus revealing genetic signals beyond commonality in volume 19 , 20 . The thalamic nuclei GWAS were also run without covarying for whole thalamus volume and are presented in the Supplementary Information.…”

Section: Resultsmentioning

confidence: 99%

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The genetic architecture of the human thalamus and its overlap with ten common brain disorders

et al. 2021

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The thalamus is a vital communication hub in the center of the brain and consists of distinct nuclei critical for consciousness and higher-order cortical functions. Structural and functional thalamic alterations are involved in the pathogenesis of common brain disorders, yet the genetic architecture of the thalamus remains largely unknown. Here, using brain scans and genotype data from 30,114 individuals, we identify 55 lead single nucleotide polymorphisms (SNPs) within 42 genetic loci and 391 genes associated with volumes of the thalamus and its nuclei. In an independent validation sample (n = 5173) 53 out of the 55 lead SNPs of the discovery sample show the same effect direction (sign test, P = 8.6e-14). We map the genetic relationship between thalamic nuclei and 180 cerebral cortical areas and find overlapping genetic architectures consistent with thalamocortical connectivity. Pleiotropy analyses between thalamic volumes and ten psychiatric and neurological disorders reveal shared variants for all disorders. Together, these analyses identify genetic loci linked to thalamic nuclei and substantiate the emerging view of the thalamus having central roles in cortical functioning and common brain disorders.

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Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

The genetic architecture of the human thalamus and its overlap with ten common brain disorders

et al. 2021

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“…Similarly, our genetic correlation results indicate that migraine was significantly correlated with mood swings, anxiety, depression, or neuroticism, consistent with a previous genetic correlation analysis study 50 . Thus, these findings suggest that migraine shares common variation risk with psychiatric disorders, such as schizophrenia, for which genome-wide significant loci involved in brain function have been reported 51 , 52 .…”

Section: Discussionmentioning

confidence: 66%

New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis

et al. 2021

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Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.

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“…To fully elucidate wakeful arousal and associated motor processes, a comprehensive investigation of functional connections of the nuclei involved is needed. Moreover, with the ever-increasing evidence of overlapping functions of several regions (Elvsåshagen et al, 2020;Eser et al, 2018), it is becoming imperative to investigate affected networks rather than single regions. However, the connectivity of arousal brainstem nuclei is understudied in living humans (Bär et al, 2016;Beliveau et al, 2015;Bianciardi et al, 2016;Coulombe et al, 2016), due to the limited sensitivity and spatial resolution of conventional imaging and to the lack of atlases of these deep tiny regions of the brain.…”

Section: Introductionmentioning

confidence: 99%

Functional connectome of arousal and motor brainstem nuclei in living humans by 7 Tesla resting-state fMRI

Singh

García‐Gomar

Stauder

et al. 2021

Preprint

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Brainstem nuclei play a pivotal role in many functions, such as arousal and motor control. Nevertheless, the connectivity of arousal and motor brainstem nuclei is understudied in living humans due to the limited sensitivity and spatial resolution of conventional imaging, and to the lack of atlases of these deep tiny regions of the brain. For a holistic comprehension of sleep, arousal and associated motor processes, we investigated in 20 healthy subjects the resting-state functional connectivity of 18 arousal and motor brainstem nuclei in living humans. To do so, we used high spatial-resolution 7 Tesla resting-state fMRI, as well as a recently developed in-vivo probabilistic atlas of these nuclei in stereotactic space. Further, we verified the translatability of our brainstem connectome approach to conventional (e.g. 3 Tesla) fMRI. Arousal brainstem nuclei displayed high interconnectivity, as well as connectivity to the thalamus, hypothalamus, basal forebrain and frontal cortex, in line with animal studies and as expected for arousal regions. Motor brainstem nuclei showed expected connectivity to the cerebellum, basal ganglia and motor cortex, as well as high interconnectivity. Comparison of 3 Tesla to 7 Tesla connectivity results indicated good translatability of our brainstem connectome approach to conventional fMRI, especially for cortical and subcortical (non-brainstem) targets and to a lesser extent for brainstem targets. The functional connectome of 18 arousal and motor brainstem nuclei with the rest of the brain might provide a better understanding of arousal, sleep and accompanying motor function in living humans in health and disease.

show abstract

The genetic architecture of human brainstem structures and their involvement in common brain disorders

Cited by 31 publications

References 72 publications

The genetic architecture of the human thalamus and its overlap with ten common brain disorders

The genetic architecture of the human thalamus and its overlap with ten common brain disorders

New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis

Functional connectome of arousal and motor brainstem nuclei in living humans by 7 Tesla resting-state fMRI

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