Genetic architecture of subcortical brain structures in 38,851 individuals

TLDR: This paper identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank.

Abstract: Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

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Satizabal
et al.
1
Genetic Architecture of Subcortical Brain Structures in Over 40,000
Individuals Worldwide
Claudia L Satizabal*
1,2
, Hieab HH Adams*
3,4
, Derrek P Hibar*
5
, Charles C White*
6,7
, Jason L Stein
5,8
,
Markus Scholz
9,10
, Murali Sargurupremraj
11
, Neda Jahanshad
5
, Albert V Smith
12,13,14
, Joshua C Bis
15
,
Xueqiu Jian
16
, Michelle Luciano
17
, Edith Hofer
18,19
, Alexander Teumer
20
, Sven J van der Lee
3
, Jingyun
Yang
21,22
, Lisa R Yanek
23
, Tom V Lee
24
, Shuo Li
25
, Yanhui Hu
26
, Jia Yu Koh
27
, John D Eicher
28
, Sylvane
Desrivières
29
, Alejandro Arias-Vasquez
30,31,32,33
, Ganesh Chauhan
11,34
, Lavinia Athanasiu
35,36
, Miguel
E Renteria
37
, Sungeun Kim
38,39,40
, David Höhn
41
, Nicola J Armstrong
42
, Qiang Chen
43
, Avram J
Holmes
44,45
, Anouk den Braber
46
, Iwona Kloszewska
47
, Micael Andersson
48,49
, Thomas Espeseth
35,50
,
Oliver Grimm
51
, Lucija Abramovic
52
, Saud Alhusaini
53,54
, Yuri Milaneschi
55
, Martina Papmeyer
56,57
,
Tomas Axelsson
58
, Stefan Ehrlich
45,59,60
, Roberto Roiz-Santiañez
61,62
, Bernd Kraemer
63
, Asta K
Håberg
64,65
, Hannah J Jones
66,67,68
, G Bruce Pike
69
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70,71
, Allison Stevens
60
, Janita
Bralten
31,33
, Meike W Vernooij
3,4
, Tamara B Harris
72
, Irina Filippi
29
, A Veronica Witte
73,74
, Tulio
Guadalupe
75,76
, Katharina Wittfeld
77,78
, Thomas H Mosley
79
, James T Becker
80
, Nhat Trung Doan
36
,
Saskia P Hagenaars
17
, Yasaman Saba
81
, Gabriel Cuellar-Partida
82
, Najaf Amin
3
, Saima Hilal
83,84
,
Kwangsik Nho
38,39,40
, Nazanin Karbalai
41
, Konstantinos Arfanakis
21,85,86
, Diane M Becker
23
, David
Ames
87,88
, Aaron L Goldman
43
, Phil H Lee
45,89,90,91,92
, Dorret I Boomsma
46
, Simon Lovestone
93,94
,
Sudheer Giddaluru
95,96
, Stephanie Le Hellard
95,96
, Manuel Mattheisen
97,98,99,100,101
, Marc M Bohlken
52
,
Dalia Kasperaviciute
102
, Lianne Schmaal
55,103,104
, Stephen M Lawrie
56
, Ingrid Agartz
36,100,105
, Esther
Walton
59,67
, Diana Tordesillas-Gutierrez
62,106
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107
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108
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70
,
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109
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31,33
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3
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29
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10,110
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31,33
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111
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77
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112
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113,114
,
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115,116
, Helena Schmidt
81
, Lachlan T Strike
82,117
, Ching-Yu Cheng
27,118
, Shannon L
All rights reserved. No reuse allowed without permission.
(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint. http://dx.doi.org/10.1101/173831doi: bioRxiv preprint first posted online Aug. 28, 2017;

Satizabal
et al.
2
Risacher
39,40
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41
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21,22,119
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120
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43,121,122
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,
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120,146
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150
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,
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108
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30,33,153
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1,2,25
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,
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159
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160,161,162
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163
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164
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165
,
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54,166
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,
169
,
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82
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46
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177,178,179
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52
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141
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,
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2,181
,
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63
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,
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72
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48,49,187
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36,100
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Facorro
61,62
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60,188
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3
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190
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70
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4,191,192
,
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11
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3,118
, Jordan W
All rights reserved. No reuse allowed without permission.
(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint. http://dx.doi.org/10.1101/173831doi: bioRxiv preprint first posted online Aug. 28, 2017;

Satizabal
et al.
3
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45,89,91,92
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5
**, Sudha Seshadri
1,2
**, M Arfan Ikram
3,4
**
1. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts,
02118, USA.
2. The Framingham Heart Study, 73 Mt Wayte Ave, Framingham, Massachusetts, 01702, USA.
3. Department of Epidemiology, Erasmus MC, Rotterdam, 3015 CE, The Netherlands.
All rights reserved. No reuse allowed without permission.
(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint. http://dx.doi.org/10.1101/173831doi: bioRxiv preprint first posted online Aug. 28, 2017;

Satizabal
et al.
4
4. Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, 3015 CE, The
Netherlands.
5. Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging & Informatics Institute,
Keck School of Medicine of University of Southern California, Los Angeles, 90292, USA.
6. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences,
Departments of Neurology and Psychiatry, Brigham and Women’s Hospital, Boston,
Massachusetts, USA.
7. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts,
USA.
8. Department of Genetics & UNC Neuroscience Center, University of North Carolina (UNC),
Chapel Hill, North Carolina, 27599, USA.
9. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107
Leipzig, Germany.
10. LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig,
Germany.
11. Inserm U1219, University of Bordeaux, Bordeaux University Hospital, Bordeaux, France.
12. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, 48109, USA.
13. Faculty of Medicine, University of Iceland, 101.
14. Icelandic Heart Association, 201 Kopavogur, Iceland.
15. Cardiovascular Health Research Unit, Department of Medicine, University of Washington,
1730 Minor Avenue / Suite 1360 / Seattle, Washington 98101, USA.
16. The University of Texas Health Science Center at Houston, Houston, Texas, 77030, USA.
17. Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of
Edinburgh, Edinburgh, EH8 9JZ, UK.
All rights reserved. No reuse allowed without permission.
(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint. http://dx.doi.org/10.1101/173831doi: bioRxiv preprint first posted online Aug. 28, 2017;

Satizabal
et al.
5
18. Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz,
Austria.
19. Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz,
Austria.
20. Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17489,
Germany.
21. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, 60612,
USA.
22. Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois,
60612, USA.
23. GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of
Medicine, Baltimore, MD 21287, USA.
24. Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
25. Department of Biostatistics, Boston University School of Public Health, Boston,
Massachusetts, 02118, USA.
26. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
27. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 168751,
Singapore.
28. National Heart, Lung and Blood Institute’s The Framingham Heart Study, Division of
Intramural Research, Population Sciences Branch, Framingham, Massachusetts, 01702, USA.
29. MRC-SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College
London, London, SE5 8AF, UK.
30. Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The
Netherlands.
All rights reserved. No reuse allowed without permission.
(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint. http://dx.doi.org/10.1101/173831doi: bioRxiv preprint first posted online Aug. 28, 2017;

Frequently asked questions

Q1. What is the role of Smarcad1 in neurogenesis?

In mouse experimental models, expression of Smarcad1 accompanies neurogenesis37; whereas in Lurcher mice, serving as a model for neurodegeneration, mutations in Grid2 are characterized by brainstem and cerebellar neurodegeneration38 resulting in ataxia39. 

Q2. What is the proximal locus of the PBX3 gene?

Another locus associated with caudate volume at 2p21 is 40kb proximal to SIX3, which encodes a transcriptional regulator with conserved neurodevelopmental roles in both vertebrates and invertebrates29. 

Q3. What are the genes that influence the volumes of the putamenand caudate?

A recent investigation identified five novel genetic loci influencing the volumes of the putamenand caudate, which pointed to genes controlling neuronal growth, apoptosis, and learning13. 

Q4. How many variants are related to the volumes of subcortical structures?

Each study related genetic variants with minor allele frequency (MAF) ≥1% to the volumes of subcortical structures (average volume for bilateral structures) using additive genetic models adjusted for sex, age, age2, total intracranial volume (total brain volume in the UKBB), and population structure. 

Q5. What is the synapse causing the Alzheimer’s disease?

The authors also identified an intronic variant in NCAM2, encoding a protein involved in olfactory system development52, levels of which are lower in hippocampal synapses of Alzheimer’s disease brains53, possibly contributing to synapse loss in Alzheimer’s disease. 

Q6. How many of the conserved fly homologs cause neuronal defects?

24.1% of the conserved fly homologs are documented to cause “neuroanatomy defective” phenotypes in flies, representing a significant (P=3.9x10-3), nearly two-fold enrichment compared to 12.9% representing all Drosophila genes associated with such phenotypes (Table S13). 

Q7. What did the authors do to examine the functional relationships between proteins encoded by their set of 62?

To explore potential functional relationships between proteins encoded by their set of 62 genes,we conducted protein-protein interaction analyses in STRING26. 

Q8. How many individuals of European ancestry were included in the study?

Their discovery sample comprised up to n=25,587 individuals of European ancestry from 45 study samples in CHARGE and ENIGMA (Table S1). 

Q9. How many variants were found in the combined meta-analysis?

In the combined meta-analysis, 21 of the 32 associations were genome-wide significant, 20 for which the strength of association increased from the discovery. 

Q10. What is the name of the gene that regulates the volume of the brainstem?

Other identified variants point to genes involved in autophagy and apoptotic processes, such as DRAM1 and FOXO3, both related to brainstem volumes. 

Q11. What is the gene that encodes the cellular adhesion molecule?

This gene encodes a conserved cellular adhesion molecule implicated in neuronal morphogenesis and cell migration based on mouse genetic studies27.