Genetic variants associated with longitudinal changes in brain structure across the lifespan

Rachel M Brouwer, Marieke Klein, Katrina L Grasby, Hugo G Schnack, Neda Jahanshad, Jalmar Teeuw, Sophia I Thomopoulos, Emma Sprooten, Carol E Franz, Nitin Gogtay, William S Kremen, Matthew S Panizzon, Loes M Olde Loohuis, Christopher D Whelan, Moji Aghajani, Clara Alloza, Dag Alnæs, Eric Artiges, Rosa Ayesa-Arriola, Gareth J Barker, Mark E Bastin, Elisabet Blok, Erlend Bøen, Isabella A Breukelaar, Joanna K Bright, Elizabeth E L Buimer, Robin Bülow, Dara M Cannon, Simone Ciufolini, Nicolas A Crossley, Christienne G Damatac, Paola Dazzan, Casper L de Mol, Sonja M C de Zwarte, Sylvane Desrivières, Covadonga M Díaz-Caneja, Nhat Trung Doan, Katharina Dohm, Juliane H Fröhner, Janik Goltermann, Antoine Grigis, Dominik Grotegerd, Laura K M Han, Mathew A Harris, Catharina A Hartman, Sarah J Heany, Walter Heindel, Dirk J Heslenfeld, Sarah Hohmann, Bernd Ittermann, Philip R Jansen, Joost Janssen, Tianye Jia, Jiyang Jiang, Christiane Jockwitz, Temmuz Karali, Daniel Keeser, Martijn G J C Koevoets, Rhoshel K Lenroot, Berend Malchow, René C W Mandl, Vicente Medel, Susanne Meinert, Catherine A Morgan, Thomas W Mühleisen, Leila Nabulsi, Nils Opel, Víctor Ortiz-García de la Foz, Bronwyn J Overs, Marie-Laure Paillère Martinot, Ronny Redlich, Tiago Reis Marques, Jonathan Repple, Gloria Roberts, Gennady V Roshchupkin, Nikita Setiaman, Elena Shumskaya, Frederike Stein, Gustavo Sudre, Shun Takahashi, Anbupalam Thalamuthu, Diana Tordesillas-Gutiérrez, Aad van der Lugt, Neeltje E M van Haren, Joanna M Wardlaw, Wei Wen, Henk-Jan Westeneng, Katharina Wittfeld, Alyssa H Zhu, Andre Zugman, Nicola J Armstrong, Gaia Bonfiglio, Janita Bralten, Shareefa Dalvie, Gail Davies, Marta Di Forti, Linda Ding, Gary Donohoe, Andreas J Forstner, Javier Gonzalez-Peñas, Joao P O F T Guimaraes, Georg Homuth, Jouke-Jan Hottenga, Maria J Knol, John B J Kwok, Stephanie Le Hellard, Karen A Mather, Yuri Milaneschi, Derek W Morris, Markus M Nöthen, Sergi Papiol, Marcella Rietschel, Marcos L Santoro, Vidar M Steen, Jason L Stein, Fabian Streit, Rick M Tankard, Alexander Teumer, Dennis van 't Ent, Dennis van der Meer, Kristel R van Eijk, Evangelos Vassos, Javier Vázquez-Bourgon, Stephanie H Witt, IMAGEN Consortium, Hieab H H Adams, Ingrid Agartz, David Ames, Katrin Amunts, Ole A Andreassen, Celso Arango, Tobias Banaschewski, Bernhard T Baune, Sintia I Belangero, Arun L W Bokde, Dorret I Boomsma, Rodrigo A Bressan, Henry Brodaty, Jan K Buitelaar, Wiepke Cahn, Svenja Caspers, Sven Cichon, Benedicto Crespo-Facorro, Simon R Cox, Udo Dannlowski, Torbjørn Elvsåshagen, Thomas Espeseth, Peter G Falkai, Simon E Fisher, Herta Flor, Janice M Fullerton, Hugh Garavan, Penny A Gowland, Hans J Grabe, Tim Hahn, Andreas Heinz, Manon Hillegers, Jacqueline Hoare, Pieter J Hoekstra, Mohammad A Ikram, Andrea P Jackowski, Andreas Jansen, Erik G Jönsson, Rene S Kahn, Tilo Kircher, Mayuresh S Korgaonkar, Axel Krug, Herve Lemaitre, Ulrik F Malt, Jean-Luc Martinot, Colm McDonald, Philip B Mitchell, Ryan L Muetzel, Robin M Murray, Frauke Nees, Igor Nenadić, Jaap Oosterlaan, Roel A Ophoff, Pedro M Pan, Brenda W J H Penninx, Luise Poustka, Perminder S Sachdev, Giovanni A Salum, Peter R Schofield, Gunter Schumann, Philip Shaw, Kang Sim, Michael N Smolka, Dan J Stein, Julian N Trollor, Leonard H van den Berg, Jan H Veldink, Henrik Walter, Lars T Westlye, Robert Whelan, Tonya White, Margaret J Wright, Sarah E Medland, Barbara Franke, Paul M Thompson, Hilleke E Hulshoff Pol, Rüdiger Brühl, Dimitri Papadopoulos Orfanos, Tomáš Paus, Sabina Millenet, Rachel M Brouwer, Marieke Klein, Katrina L Grasby, Hugo G Schnack, Neda Jahanshad, Jalmar Teeuw, Sophia I Thomopoulos, Emma Sprooten, Carol E Franz, Nitin Gogtay, William S Kremen, Matthew S Panizzon, Loes M Olde Loohuis, Christopher D Whelan, Moji Aghajani, Clara Alloza, Dag Alnæs, Eric Artiges, Rosa Ayesa-Arriola, Gareth J Barker, Mark E Bastin, Elisabet Blok, Erlend Bøen, Isabella A Breukelaar, Joanna K Bright, Elizabeth E L Buimer, Robin Bülow, Dara M Cannon, Simone Ciufolini, Nicolas A Crossley, Christienne G Damatac, Paola Dazzan, Casper L de Mol, Sonja M C de Zwarte, Sylvane Desrivières, Covadonga M Díaz-Caneja, Nhat Trung Doan, Katharina Dohm, Juliane H Fröhner, Janik Goltermann, Antoine Grigis, Dominik Grotegerd, Laura K M Han, Mathew A Harris, Catharina A Hartman, Sarah J Heany, Walter Heindel, Dirk J Heslenfeld, Sarah Hohmann, Bernd Ittermann, Philip R Jansen, Joost Janssen, Tianye Jia, Jiyang Jiang, Christiane Jockwitz, Temmuz Karali, Daniel Keeser, Martijn G J C Koevoets, Rhoshel K Lenroot, Berend Malchow, René C W Mandl, Vicente Medel, Susanne Meinert, Catherine A Morgan, Thomas W Mühleisen, Leila Nabulsi, Nils Opel, Víctor Ortiz-García de la Foz, Bronwyn J Overs, Marie-Laure Paillère Martinot, Ronny Redlich, Tiago Reis Marques, Jonathan Repple, Gloria Roberts, Gennady V Roshchupkin, Nikita Setiaman, Elena Shumskaya, Frederike Stein, Gustavo Sudre, Shun Takahashi, Anbupalam Thalamuthu, Diana Tordesillas-Gutiérrez, Aad van der Lugt, Neeltje E M van Haren, Joanna M Wardlaw, Wei Wen, Henk-Jan Westeneng, Katharina Wittfeld, Alyssa H Zhu, Andre Zugman, Nicola J Armstrong, Gaia Bonfiglio, Janita Bralten, Shareefa Dalvie, Gail Davies, Marta Di Forti, Linda Ding, Gary Donohoe, Andreas J Forstner, Javier Gonzalez-Peñas, Joao P O F T Guimaraes, Georg Homuth, Jouke-Jan Hottenga, Maria J Knol, John B J Kwok, Stephanie Le Hellard, Karen A Mather, Yuri Milaneschi, Derek W Morris, Markus M Nöthen, Sergi Papiol, Marcella Rietschel, Marcos L Santoro, Vidar M Steen, Jason L Stein, Fabian Streit, Rick M Tankard, Alexander Teumer, Dennis van 't Ent, Dennis van der Meer, Kristel R van Eijk, Evangelos Vassos, Javier Vázquez-Bourgon, Stephanie H Witt, IMAGEN Consortium, Hieab H H Adams, Ingrid Agartz, David Ames, Katrin Amunts, Ole A Andreassen, Celso Arango, Tobias Banaschewski, Bernhard T Baune, Sintia I Belangero, Arun L W Bokde, Dorret I Boomsma, Rodrigo A Bressan, Henry Brodaty, Jan K Buitelaar, Wiepke Cahn, Svenja Caspers, Sven Cichon, Benedicto Crespo-Facorro, Simon R Cox, Udo Dannlowski, Torbjørn Elvsåshagen, Thomas Espeseth, Peter G Falkai, Simon E Fisher, Herta Flor, Janice M Fullerton, Hugh Garavan, Penny A Gowland, Hans J Grabe, Tim Hahn, Andreas Heinz, Manon Hillegers, Jacqueline Hoare, Pieter J Hoekstra, Mohammad A Ikram, Andrea P Jackowski, Andreas Jansen, Erik G Jönsson, Rene S Kahn, Tilo Kircher, Mayuresh S Korgaonkar, Axel Krug, Herve Lemaitre, Ulrik F Malt, Jean-Luc Martinot, Colm McDonald, Philip B Mitchell, Ryan L Muetzel, Robin M Murray, Frauke Nees, Igor Nenadić, Jaap Oosterlaan, Roel A Ophoff, Pedro M Pan, Brenda W J H Penninx, Luise Poustka, Perminder S Sachdev, Giovanni A Salum, Peter R Schofield, Gunter Schumann, Philip Shaw, Kang Sim, Michael N Smolka, Dan J Stein, Julian N Trollor, Leonard H van den Berg, Jan H Veldink, Henrik Walter, Lars T Westlye, Robert Whelan, Tonya White, Margaret J Wright, Sarah E Medland, Barbara Franke, Paul M Thompson, Hilleke E Hulshoff Pol, Rüdiger Brühl, Dimitri Papadopoulos Orfanos, Tomáš Paus, Sabina Millenet

Abstract

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

Trial registration: ClinicalTrials.gov NCT02534363 NCT02305832.

Conflict of interest statement

Competing interests:

Other authors declare no conflict of interest.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Figures

Extended Data Fig. 1. Demographics and analysis
Extended Data Fig. 1. Demographics and analysis
Overview of demographics (left). Per cohort, an age distribution is displayed, based on mean and standard deviation of the age at baseline. Cohorts of European ancestry are displayed in green, non-European cohorts are displayed in yellow. On the right, the total number of included subjects is displayed and a pie-chart of the distribution of diagnostic groups (pink) and subjects not belonging to diagnostic groups - often healthy subjects (aqua). Overview of analysis pipeline (right).
Extended Data Fig. 2. Correlations between change…
Extended Data Fig. 2. Correlations between change rates
Pearson correlations between rates of change and between baseline intracranial volume and rates of change in the largest adolescent cohort (top, N = 1068) and the largest cohort in older age (bottom, N = 624) in phase 1. The size of the correlations is displayed by color and size of the circles.
Figure 1:
Figure 1:
Phenotypic brain changes throughout the lifespan. Visualization of growth and decline of brain structures throughout the lifespan. The subcortical structures are shown in exploded view.
Figure 2:
Figure 2:
Annual rates of change Δ per cohort for each structure (a-o). The estimated trajectories with 95% confidence intervals (in green) are displayed in the top row. Mean values of individual cohorts are displayed as points, with error bars representing standard errors displayed in grey. The size of the points represents the relative size of the cohorts, total sample size N=15640. Means and standard deviations are based on raw data – no covariates were included. Cohorts that were added in phase 2 are displayed in grey. Only cohorts that satisfy N>75 and mean interval > 0.5 years are shown. The estimated trajectories of the volumes themselves are displayed in the bottom row, for all subjects (solid line) and for subjects not part of diagnostic groups (dashed line).
Figure 3:
Figure 3:
Genetic effects on rates of brain changes throughout the lifespan. Genome-wide significant SNPs and genes with effects on brain changes at their respective loci across the human genome, from phase 2 (total N=15,100). This plot was created using PhenoGram (http://visualization.ritchielab.org).
Figure 4:
Figure 4:
Summary of findings for two top-SNPs. Shown here is a summary of findings for a top-SNP of an age independent effect (rs72772746; intron to GPR139; associated with rate of change of lateral ventricle volume; left column) and a top-SNP of an age dependent effect (13:72353395; intron to DACH1; associated with rate of change in cerebral white matter volume; right column). Displayed are the locus plots (a) and (d), forest plot (b; total N = 14593, means and 95% confidence intervals are displayed for each cohort; confidence intervals that are outside the axis of the plot are marked with an arrow) and plot of meta-regression (e; total N = 13864, center of the circles represent the effect size of the tested allele for each cohort, radius of the circles are proportional to sample size) and inferred lifespan trajectories for carriers (in red) and non-carriers of the effect allele (in black) (c) and (f). Note that 13:72353395 was not in the reference dataset containing LD structure; the displayed LD structure is based on 13:7234009, R2 = 0.87 with the top-SNP.
Figure 5:
Figure 5:
Genetic overlap with other phenotypes. P-values for pleiotropy between change rates of structural brain measures (rows, indicated by Δ for change rate) and neuropsychiatric, disease-related and psychological traits (columns on the left). P-values for pleiotropy between change rates of structural brain measures and head size (intracranial volume) and the cross-sectional brain measure are displayed on the right. The colour legend is displayed on the right, indicating the -log10 p-value. Significant overlap (p < 1.6e-04; obtained through permutation testing, two-sided, Bonferroni corrected) is marked with *. P-values underlying this figure can be found in Supplemental Table 16.

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