Shared Genetic Determinants Between the Brain Functional Connectome and Psychiatric Disorders

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Daniel Roelfs

@dthroelfs

University of Oslo

No disclosures to declare

Slide added to comply with ACCME accreditation guidelines

Background

• Psychiatric conditions are highly polygenic and complex¹
• Psychiatric conditions share symptoms and genetic profiles²
• MRI studies show that structural and functional changes are widespread across the brain³
• Investigate distributed nature of genetic effects in the brain and its associations with psychiatric conditions

1. Anttila et al. Science (2018), Sullivan & Geschwind Cell (2019), Paulus & Thompson JAMA Psychiatry (2019)
2. Plana-Ripoll et al. JAMA Psychiatry (2019), Bulik-Sullivan et al. Nature Genetics (2015)
3. Petterson-Yeo et al. Neurosci. Biobehav. Rev. (2011), Arnatkeviciute et al. NeuroImage (2021)

Dataset

Why use fMRI?

• Changes in fMRI features associated with many psychiatric conditions¹
• Changes in structural MRI features have been used to study genetic architecture of conditions²
• fMRI data provides insight into brain function rather than structure
• Integrate changes in fMRI features with processes underlying psychiatric conditions

1. e.g. Brakowski et al. J. Psychiatr. Res. (2017), Syan et al. J. Psychiatry. Neurosci. (2018), etc.
2. Elliott et al. Nature (2018), Friston et al. Schizophr. Res. (2016)

Brain connectivity measures

Brain connectivity measures

Brain functional connectivity

UK Biobank Brain Imaging - Connectome Browser (d25)

Multivariate GWAS

1. van der Meer et al. Nature Communications (2020), github.com/precimed/mostest

What is MOSTest?

• Identifies small and distributed effects not detectable in univariate GWAS
• Takes univariate z-scores for each SNP across all phenotypes
• 
  Integrates into multivariate test statistic through Mahalanobis distance

Details in van der Meer et al. Nature Communications (2020), github.com/precimed/mostest

MOSTest Manhattan plots

Functional connectivity

MOSTest	15 loci
Min-P	2 loci

Node variance

MOSTest	5 loci
Min-P	3 loci

Genetic overlap

1. PleioFDR, Andreassen et al. PLoS Genetics (2019), github.com/precimed/pleiofdr

Conjunctional FDR

Conjunctional FDR

Mapped genes

• Functional annotation and mapping of genome-wide assocation studies (FUMA¹)
• 
  Gene set mapped from the significant loci in the GWAS
• 
  Compare identified genes to genes involved in synapses (e.g. BDNF, NRXN1 etc.)²
  

1. Watanabe et al. Nature Communications (2017)
2. SynGO, Koopmans et al. Neuron (2019)

Mapped biological processes

Reactome Pathway Database, Jassal et al. Nucleic Acids Res. (2020)

Conclusion

• Genetic overlap between the brain functional connectome and psychiatric conditions
• Link shared genetic loci back to biological processes implicated in psychiatric conditions
• Identified a number of synaptic processes associated with shared loci

Thanks to

ERA-NET

SYNSCHIZ
Linking synaptic dysfunction to disease mechanisms in schizophrenia