Paper II

Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders

We applied a multivariate GWAS framework implemented through MOSTest¹ to fMRI features on FC (210 features) and temporal node variance (21 features) from 30,701 individuals in the UKB. We identified 15 independent genetic loci significantly associated (p < 5e^-8) with FC and 5 loci associated with temporal node variance through the multivariate analysis. The univariate stream identified 2 and 3 independent loci respectively. In an independent replication sample nearly all of these loci replicated at nominal p-value (14/15, 93%, p < 0.05). Figure 26.1 panel A shows the Miami plots for both features for both the multivariate and univariate stream. Figure 26.1 panel B shows the distributed nature of these loci across the brain, where a single locus is significantly (p < 0.05) associated with a number of univariate comparisons.

Figure 26.1: A) Genetic discoveries from the MOSTest analysis showing the multivariate results on the top row and the univariate p-values for each of the lead SNPs in each locus discovered by the multivariate stream. B) Nominally significant connections from the univariate stream for each of the genome-wide significant loci identified by MOSTest. C) Replication analysis showing the proportion of replicated loci in the replications sample. Figure originally published in Roelfs et al.².

Next we compared the MOSTest summary statistics on FC and node variance with seven psychiatric disorders (ADHD, ASD, ANX, BIP, MD, PTSD, and SCZ) using conjFDR analysis. As indicated in Figure 26.2, we found overlapping loci with the brain connectivity features for six out of the seven disorders in this analysis. We found the largest overlap with SCZ, 43 overlapping loci for FC and 22 for node variance. Comparisons with a negative control trait, in this case vitamin D levels (N = 79,366) showed 2 overlapping loci with FC and none with node variance.

Figure 26.2: conjFDR analysis showing the shared genetic architecture between the multivariate brain phenotype and psychiatric disorders. Originally published in Roelfs et al.².

Using FUMA³ we mapped the shared loci between the imaging features and the psychiatric conditions to the genes associated with these loci. This yielded 180 genes associated with any of the features or disorders in our analysis. Next, we analyzed these genes with the SynGO⁴ tool to identify associations of these genes with synaptic processes. We found associations with synaptic functioning for 23 out of 180 genes, such as bdnf, a major regulator of synaptic transmission and synaptic plasticity⁵, and nrxn1, which plays a role in the formation of synapstic connections⁶. The ability to implicate these synapse-related genes provides further support from an imaging-genetics perspective for the dysconnectivity hypothesis of psychiatric disorders, as discussed more closely in the Discussion ?sec-discussion section of this thesis.

1.

van der Meer D, Frei O, Kaufmann T, Shadrin AA, Devor A, Smeland OB, et al. Understanding the genetic determinants of the brain with MOSTest. Nature Communications [Internet]. 2020 Jul 14;11(1):3512. Available from: https://doi.org/10.1038/s41467-020-17368-1

2.

Roelfs D, van der Meer D, Alnæs D, Frei O, Shadrin AA, Loughnan R, et al. Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders. Nature Mental Health [Internet]. 2024 Feb 1;2(2):189–99. Available from: https://doi.org/10.1038/s44220-023-00190-1

3.

Watanabe K, Taskesen E, van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nature Communications [Internet]. 2017 Nov 28;8(1):1826. Available from: https://doi.org/10.1038/s41467-017-01261-5

4.

Koopmans F, van Nierop P, Andres-Alonso M, Byrnes A, Cijsouw T, Coba MP, et al. SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse. Neuron [Internet]. 2019 Jul 17;103(2):217–234.e4. Available from: https://www.sciencedirect.com/science/article/pii/S0896627319304271

5.

Dean C, Liu H, Dunning FM, Chang PY, Jackson MB, Chapman ER. Synaptotagmin-IV modulates synaptic function and long-term potentiation by regulating BDNF release. Nat Neurosci. 2009 Jun;12(6):767–76.

6.

Dean C, Scholl FG, Choih J, DeMaria S, Berger J, Isacoff E, et al. Neurexin mediates the assembly of presynaptic terminals. Nat Neurosci. 2003 Jul;6(7):708–16.