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Alagöz, G., Molz, B., Eising, E., Schijven, D., Francks, C., Jason L., S., & Fisher, S. E. (2022). Using neuroimaging genomics to investigate the evolution of human brain structure. Proceedings of the National Academy of Sciences of the United States of America, 119(40): e2200638119. doi:10.1073/pnas.2200638119.
Abstract
Alterations in brain size and organization represent some of the most distinctive changes in the emergence of our species. Yet, there is limited understanding of how genetic factors contributed to altered neuroanatomy during human evolution. Here, we analyze neuroimaging and genetic data from up to 30,000 people in the UK Biobank and integrate with genomic annotations for different aspects of human evolution, including those based on ancient DNA and comparative genomics. We show that previously reported signals of recent polygenic selection for cortical anatomy are not replicable in a more ancestrally homogeneous sample. We then investigate relationships between evolutionary annotations and common genetic variants shaping cortical surface area and white-matter connectivity for each hemisphere. Our analyses identify single-nucleotide polymorphism heritability enrichment in human-gained regulatory elements that are active in early brain development, affecting surface areas of several parts of the cortex, including left-hemispheric speech-associated regions. We also detect heritability depletion in genomic regions with Neanderthal ancestry for connectivity of the uncinate fasciculus; this is a white-matter tract involved in memory, language, and socioemotional processing with relevance to neuropsychiatric disorders. Finally, we show that common genetic loci associated with left-hemispheric pars triangularis surface area overlap with a human-gained enhancer and affect regulation of ZIC4, a gene implicated in neurogenesis. This work demonstrates how genomic investigations of present-day neuroanatomical variation can help shed light on the complexities of our evolutionary past.Additional information
supplementary information -
Kong, X., Postema, M., Guadalupe, T., De Kovel, C. G. F., Boedhoe, P. S. W., Hoogman, M., Mathias, S. R., Van Rooij, D., Schijven, D., Glahn, D. C., Medland, S. E., Jahanshad, N., Thomopoulos, S. I., Turner, J. A., Buitelaar, J., Van Erp, T. G. M., Franke, B., Fisher, S. E., Van den Heuvel, O. A., Schmaal, L. and 2 moreKong, X., Postema, M., Guadalupe, T., De Kovel, C. G. F., Boedhoe, P. S. W., Hoogman, M., Mathias, S. R., Van Rooij, D., Schijven, D., Glahn, D. C., Medland, S. E., Jahanshad, N., Thomopoulos, S. I., Turner, J. A., Buitelaar, J., Van Erp, T. G. M., Franke, B., Fisher, S. E., Van den Heuvel, O. A., Schmaal, L., Thompson, P. M., & Francks, C. (2022). Mapping brain asymmetry in health and disease through the ENIGMA consortium. Human Brain Mapping, 43(1), 167-181. doi:10.1002/hbm.25033.
Abstract
Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last four years, the ENIGMA-Laterality Working Group has published six studies of grey matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average asymmetry was achieved, including an
intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA’s multidataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for grey matter asymmetry based on large, international,
samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders:Autism Spectrum Disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; Pediatric Obsessive-Compulsive Disorder was associated with altered subcortical asymmetry; Major Depressive Disorder was not significantly associated with changes
of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders. -
Maihofer, A. X., Choi, K. W., Coleman, J. R., Daskalakis, N. P., Denckla, C. A., Ketema, E., Morey, R. A., Polimanti, R., Ratanatharathorn, A., Torres, K., Wingo, A. P., Zai, C. C., Aiello, A. E., Almli, L. M., Amstadter, A. B., Andersen, S. B., Andreassen, O. A., Arbisi, P. A., Ashley-Koch, A. E., Austin, S. B. and 161 moreMaihofer, A. X., Choi, K. W., Coleman, J. R., Daskalakis, N. P., Denckla, C. A., Ketema, E., Morey, R. A., Polimanti, R., Ratanatharathorn, A., Torres, K., Wingo, A. P., Zai, C. C., Aiello, A. E., Almli, L. M., Amstadter, A. B., Andersen, S. B., Andreassen, O. A., Arbisi, P. A., Ashley-Koch, A. E., Austin, S. B., Avdibegovic, E., Borglum, A. D., Babic, D., Bækvad-Hansen, M., Baker, D. G., Beckham, J. C., Bierut, L. J., Bisson, J. I., Boks, M. P., Bolger, E. A., Bradley, B., Brashear, M., Breen, G., Bryant, R. A., Bustamante, A. C., Bybjerg-Grauholm, J., Calabrese, J. R., Caldas-de-Almeida, J. M., Chen, C.-Y., Dale, A. M., Dalvie, S., Deckert, J., Delahanty, D. L., Dennis, M. F., Disner, S. G., Domschke, K., Duncan, L. E., Dzubur Kulenovic, A., Erbes, C. R., Evans, A., Farrer, L. A., Feeny, N. C., Flory, J. D., Forbes, D., Franz, C. E., Galea, S., Garrett, M. E., Gautam, A., Gelaye, B., Gelernter, J., Geuze, E., Gillespie, C. F., Goçi, A., Gordon, S. D., Guffanti, G., Hammamieh, R., Hauser, M. A., Heath, A. C., Hemmings, S. M., Hougaard, D. M., Jakovljevic, M., Jett, M., Johnson, E. O., Jones, I., Jovanovic, T., Qin, X.-J., Karstoft, K.-I., Kaufman, M. L., Kessler, R. C., Khan, A., Kimbrel, N. A., King, A. P., Koen, N., Kranzler, H. R., Kremen, W. S., Lawford, B. R., Lebois, L. A., Lewis, C., Liberzon, I., Linnstaedt, S. D., Logue, M. W., Lori, A., Lugonja, B., Luykx, J. J., Lyons, M. J., Maples-Keller, J. L., Marmar, C., Martin, N. G., Maurer, D., Mavissakalian, M. R., McFarlane, A., McGlinchey, R. E., McLaughlin, K. A., McLean, S. A., Mehta, D., Mellor, R., Michopoulos, V., Milberg, W., Miller, M. W., Morris, C. P., Mors, O., Mortensen, P. B., Nelson, E. C., Nordentoft, M., Norman, S. B., O’Donnell, M., Orcutt, H. K., Panizzon, M. S., Peters, E. S., Peterson, A. L., Peverill, M., Pietrzak, R. H., Polusny, M. A., Rice, J. P., Risbrough, V. B., Roberts, A. L., Rothbaum, A. O., Rothbaum, B. O., Roy-Byrne, P., Ruggiero, K. J., Rung, A., Rutten, B. P., Saccone, N. L., Sanchez, S. E., Schijven, D., Seedat, S., Seligowski, A. V., Seng, J. S., Sheerin, C. M., Silove, D., Smith, A. K., Smoller, J. W., Sponheim, S. R., Stein, D. J., Stevens, J. S., Teicher, M. H., Thompson, W. K., Trapido, E., Uddin, M., Ursano, R. J., van den Heuvel, L. L., Van Hooff, M., Vermetten, E., Vinkers, C., Voisey, J., Wang, Y., Wang, Z., Werge, T., Williams, M. A., Williamson, D. E., Winternitz, S., Wolf, C., Wolf, E. J., Yehuda, R., Young, K. A., Young, R. M., Zhao, H., Zoellner, L. A., Haas, M., Lasseter, H., Provost, A. C., Salem, R. M., Sebat, J., Shaffer, R. A., Wu, T., Ripke, S., Daly, M. J., Ressler, K. J., Koenen, K. C., Stein, M. B., & Nievergelt, C. M. (2022). Enhancing discovery of genetic variants for posttraumatic stress disorder through integration of quantitative phenotypes and trauma exposure information. Biological Psychiatry, 91(7), 626-636. doi:10.1016/j.biopsych.2021.09.020.
Abstract
Background
Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).
Methods
A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms.
Results
GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program.
Conclusions
Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. -
Van der Spek, J., Den Hoed, J., Snijders Blok, L., Dingemans, A. J. M., Schijven, D., Nellaker, C., Venselaar, H., Astuti, G. D. N., Barakat, T. S., Bebin, E. M., Beck-Wödl, S., Beunders, G., Brown, N. J., Brunet, T., Brunner, H. G., Campeau, P. M., Čuturilo, G., Gilissen, C., Haack, T. B., Hüning, I. and 26 moreVan der Spek, J., Den Hoed, J., Snijders Blok, L., Dingemans, A. J. M., Schijven, D., Nellaker, C., Venselaar, H., Astuti, G. D. N., Barakat, T. S., Bebin, E. M., Beck-Wödl, S., Beunders, G., Brown, N. J., Brunet, T., Brunner, H. G., Campeau, P. M., Čuturilo, G., Gilissen, C., Haack, T. B., Hüning, I., Husain, R. A., Kamien, B., Lim, S. C., Lovrecic, L., Magg, J., Maver, A., Miranda, V., Monteil, D. C., Ockeloen, C. W., Pais, L. S., Plaiasu, V., Raiti, L., Richmond, C., Rieß, A., Schwaibold, E. M. C., Simon, M. E. H., Spranger, S., Tan, T. Y., Thompson, M. L., De Vries, B. B., Wilkins, E. J., Willemsen, M. H., Francks, C., Vissers, L. E. L. M., Fisher, S. E., & Kleefstra, T. (2022). Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome. Genetics in Medicine, 24(6), 1283-1296. doi:10.1016/j.gim.2022.02.014.
Abstract
Purpose
Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed.
Methods
We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome.
Results
Computational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted.
Conclusion
Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease. -
Hebebrand, J., Peters, T., Schijven, D., Hebebrand, M., Grasemann, C., Winkler, T. W., Heid, I. M., Antel, J., Föcker, M., Tegeler, L., Brauner, L., Adan, R. A., Luykx, J. J., Correll, C. U., König, I. R., Hinney, A., & Libuda, L. (2018). The role of genetic variation of human metabolism for BMI, mental traits and mental disorders. Molecular Metabolism, 12, 1-11. doi:10.1016/j.molmet.2018.03.015.
Abstract
Objective
The aim was to assess whether loci associated with metabolic traits also have a significant role in BMI and mental traits/disorders
Methods
We first assessed the number of single nucleotide polymorphisms (SNPs) with genome-wide significance for human metabolism (NHGRI-EBI Catalog). These 516 SNPs (216 independent loci) were looked-up in genome-wide association studies for association with body mass index (BMI) and the mental traits/disorders educational attainment, neuroticism, schizophrenia, well-being, anxiety, depressive symptoms, major depressive disorder, autism-spectrum disorder, attention-deficit/hyperactivity disorder, Alzheimer's disease, bipolar disorder, aggressive behavior, and internalizing problems. A strict significance threshold of p < 6.92 × 10−6 was based on the correction for 516 SNPs and all 14 phenotypes, a second less conservative threshold (p < 9.69 × 10−5) on the correction for the 516 SNPs only.
Results
19 SNPs located in nine independent loci revealed p-values < 6.92 × 10−6; the less strict criterion was met by 41 SNPs in 24 independent loci. BMI and schizophrenia showed the most pronounced genetic overlap with human metabolism with three loci each meeting the strict significance threshold. Overall, genetic variation associated with estimated glomerular filtration rate showed up frequently; single metabolite SNPs were associated with more than one phenotype. Replications in independent samples were obtained for BMI and educational attainment.
Conclusions
Approximately 5–10% of the regions involved in the regulation of blood/urine metabolite levels seem to also play a role in BMI and mental traits/disorders and related phenotypes. If validated in metabolomic studies of the respective phenotypes, the associated blood/urine metabolites may enable novel preventive and therapeutic strategies. -
Schijven, D., Kofink, D., Tragante, V., Verkerke, M., Pulit, S. L., Kahn, R. S., Veldink, J. H., Vinkers, C. H., Boks, M. P., & Luykx, J. J. (2018). Comprehensive pathway analyses of schizophrenia risk loci point to dysfunctional postsynaptic signaling. Schizophrenia Research, 199, 195-202. doi:10.1016/j.schres.2018.03.032.
Abstract
Large-scale genome-wide association studies (GWAS) have implicated many low-penetrance loci in schizophrenia. However, its pathological mechanisms are poorly understood, which in turn hampers the development of novel pharmacological treatments. Pathway and gene set analyses carry the potential to generate hypotheses about disease mechanisms and have provided biological context to genome-wide data of schizophrenia. We aimed to examine which biological processes are likely candidates to underlie schizophrenia by integrating novel and powerful pathway analysis tools using data from the largest Psychiatric Genomics Consortium schizophrenia GWAS (N=79,845) and the most recent 2018 schizophrenia GWAS (N=105,318). By applying a primary unbiased analysis (Multi-marker Analysis of GenoMic Annotation; MAGMA) to weigh the role of biological processes from the Molecular Signatures Database (MSigDB), we identified enrichment of common variants in synaptic plasticity and neuron differentiation gene sets. We supported these findings using MAGMA, Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA) and Interval Enrichment Analysis (INRICH) on detailed synaptic signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and found enrichment in mainly the dopaminergic and cholinergic synapses. Moreover, shared genes involved in these neurotransmitter systems had a large contribution to the observed enrichment, protein products of top genes in these pathways showed more direct and indirect interactions than expected by chance, and expression profiles of these genes were largely similar among brain tissues. In conclusion, we provide strong and consistent genetics and protein-interaction informed evidence for the role of postsynaptic signaling processes in schizophrenia, opening avenues for future translational and psychopharmacological studies.
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