Vertex-wise multivariate genome-wide association study identifies 780 unique genetic loci associated with cortical morphology

Alexey A Shadrin¹, Tobias Kaufmann², Dennis van der Meer³, Clare E Palmer⁴, Carolina Makowski⁵, Robert Loughnan⁶, Terry L Jernigan⁷, Tyler M Seibert⁸, Donald J Hagler⁵, Olav B Smeland², Ehsan Motazedi², Yunhan Chu², Aihua Lin², Weiqiu Cheng², Guy Hindley², Wesley K Thompson⁹, Chun C Fan¹⁰, Dominic Holland¹¹, Lars T Westlye¹², Oleksandr Frei², Ole A Andreassen¹³, Anders M Dale¹⁴

Affiliations

¹ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway. Electronic address: a.a.shadrin@medisin.uio.no.
² NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway.
³ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, the Netherlands.
⁴ Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA.
⁵ Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA.
⁶ Department of Cognitive Science, University of California San Diego, La Jolla, CA 92037, USA.
⁷ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA; Center for Human Development, University of California San Diego, La Jolla, CA 92037, USA; Department of Cognitive Science, University of California San Diego, La Jolla, CA 92037, USA.
⁸ Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA; Department of Bioengineering, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92037, USA.
⁹ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92037, USA.
¹⁰ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA.
¹¹ Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA.
¹² NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Psychology, University of Oslo, Oslo, Norway.
¹³ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway. Electronic address: ole.andreassen@medisin.uio.no.
¹⁴ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA. Electronic address: andersmdale@gmail.com.

PMID: 34560273
PMCID: PMC8785963
DOI: 10.1016/j.neuroimage.2021.118603

Vertex-wise multivariate genome-wide association study identifies 780 unique genetic loci associated with cortical morphology

Alexey A Shadrin et al. Neuroimage. 2021.

. 2021 Dec 1:244:118603.

doi: 10.1016/j.neuroimage.2021.118603. Epub 2021 Sep 21.

Authors

Affiliations

¹ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway. Electronic address: a.a.shadrin@medisin.uio.no.
² NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway.
³ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, the Netherlands.
⁴ Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA.
⁵ Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA.
⁶ Department of Cognitive Science, University of California San Diego, La Jolla, CA 92037, USA.
⁷ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA; Center for Human Development, University of California San Diego, La Jolla, CA 92037, USA; Department of Cognitive Science, University of California San Diego, La Jolla, CA 92037, USA.
⁸ Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA; Department of Bioengineering, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92037, USA.
⁹ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92037, USA.
¹⁰ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA.
¹¹ Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA.
¹² NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Psychology, University of Oslo, Oslo, Norway.
¹³ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway. Electronic address: ole.andreassen@medisin.uio.no.
¹⁴ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA. Electronic address: andersmdale@gmail.com.

PMID: 34560273
PMCID: PMC8785963
DOI: 10.1016/j.neuroimage.2021.118603

Abstract

Brain morphology has been shown to be highly heritable, yet only a small portion of the heritability is explained by the genetic variants discovered so far. Here we extended the Multivariate Omnibus Statistical Test (MOSTest) and applied it to genome-wide association studies (GWAS) of vertex-wise structural magnetic resonance imaging (MRI) cortical measures from N=35,657 participants in the UK Biobank. We identified 695 loci for cortical surface area and 539 for cortical thickness, in total 780 unique genetic loci associated with cortical morphology robustly replicated in 8,060 children of mixed ethnicity from the Adolescent Brain Cognitive Development (ABCD) Study®. This reflects more than 8-fold increase in genetic discovery at no cost to generalizability compared to the commonly used univariate GWAS methods applied to region of interest (ROI) data. Functional follow up including gene-based analyses implicated 10% of all protein-coding genes and pointed towards pathways involved in neurogenesis and cell differentiation. Power analysis indicated that applying the MOSTest to vertex-wise structural MRI data triples the effective sample size compared to conventional univariate GWAS approaches. The large boost in power obtained with the vertex-wise MOSTest together with pronounced replication rates and highlighted biologically meaningful pathways underscores the advantage of multivariate approaches in the context of highly distributed polygenic architecture of the human brain.

Keywords: Cortical surface area; Cortical thickness; Distributed polygenic architecture; Genome-wide association study; Multivariate vertex-wise analysis.

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Conflict of interest statement

Declaration of Competing Interest Dr. Andreassen has received speaker's honorarium from Lundbeck, and is a consultant to HealthLytix. Dr. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. The other authors declare no competing interests.

Figures

**Figure 1.. Manhattan plots for cortical surface area and cortical thickness.**
(A) Area, MOSTest, vertex-wise: N=695 loci. (B) Area, MOSTest, ROI: N=370 loci. (C) Area, min-P, ROI: N=88 loci. (D) Thickness, MOSTest, vertex-wise: N=539 loci. (E) Thickness, MOSTest, ROI: N=181 loci. (F) Thickness, min-P, ROI: N=44 loci. Black dotted horizontal lines show genome-wide significance threshold (P=5E-8). Loci; independent genome-wide significant (P<5E-8). Y-axes are truncated at −log10(P)=17.2 to highlight the region around genome-wide significance threshold. ROI = region of interest.

**Figure 2.. Estimated percent of additive genetic variance explained by genome-wide significant SNPs as a function of sample size.**
Percentages of genetic variance explained by identified SNPs (p<5E-8) from multivariate GWAS (MOSTest VW) of area (A) and thickness (B) with current sample size (N=35,657, vertical dotted line) are shown in parentheses, with MOSTest ROI and min-P ROI for comparison. VW = vertex-wise. ROI = region of interest.

**Figure 3.. Gene-set analyses with MAGMA.**
Results from the gene-set analysis based on multivariate GWAS on area (A) and thickness (B). Ten most significant Gene Ontology sets (N=7,343) in the vertex-wise MOSTest analysis are listed on the y-axis, in comparison with MOSTest ROI and min-P ROI. Corresponding uncorrected −log10(p-values) are shown on the x-axis. P-values were obtained using MAGMA analysis as implemented in FUMA. Vertical dotted line shows Bonferroni correction threshold (p=0.05/7343). VW = vertex-wise. ROI = region of interest.

**Figure 4.. Lateral view of the cortex, depicting the color-coded vertex-wise z-values for the top genetic loci identified in the discovery vertex-wise MOSTest analysis.**
(A): top lead variant (rs34680120, chr15:39664000, effect direction of C allele is shown, frequency of C allele = 0.94) associated with cortical surface area in discovery (top) and replication (bottom) samples. (B): top lead variant (rs8033007, chr15:39619661, effect direction of G allele is shown, frequency of G allele = 0.91) associated with cortical thickness in discovery (top) and replication (bottom) samples.

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Vertex-wise multivariate genome-wide association study identifies 780 unique genetic loci associated with cortical morphology

Affiliations

Vertex-wise multivariate genome-wide association study identifies 780 unique genetic loci associated with cortical morphology

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources