. 2023 Nov 20;10(1):813.

doi: 10.1038/s41597-023-02645-7.

Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases

McKinzie A Garrison¹, Yeongjun Jang², Taejeong Bae², Adriana Cherskov³, Sarah B Emery⁴, Liana Fasching⁵, Attila Jones^{6

7}, John B Moldovan⁴, Cindy Molitor⁸, Sirisha Pochareddy³, Mette A Peters⁸, Joo Heon Shin^{9

10}, Yifan Wang⁴, Xiaoxu Yang^{11

12}, Schahram Akbarian^{13

14}, Andrew Chess^{6

7

13

14}, Fred H Gage¹⁵, Joseph G Gleeson^{11

12}, Jeffrey M Kidd^{4

16}, Michael McConnell⁹, Ryan E Mills^{4

16}, John V Moran^{4

17}, Peter J Park¹⁸, Nenad Sestan³, Alexander E Urban^{19

20}, Flora M Vaccarino^{3

5}, Christopher A Walsh²¹, Daniel R Weinberger^{9

10

22

23

24}, Sarah J Wheelan^{25

26}, Alexej Abyzov²⁷; BSMN Consortium

Collaborators, Affiliations

Collaborators

BSMN Consortium:
Aitor Serres Amero, Danny Antaki, Dan Averbuj, Laurel Ball, Sara Bizzotto, Craig Bohrson, Rebeca Borges-Monroy, Martin Breuss, Sean Cho, Chong Chu, Changuk Chung, Isidro Cortes-Ciriano, Michael Coulter, Kenneth Daily, Caroline Dias, Alissa D'Gama, Yanmei Dou, Jennifer Erwin, Diane A Flasch, Trenton J Frisbie, Alon Galor, Javier Ganz, Doga Gulhan, Robert Hill, August Yue Huang, Andrew Jaffe, Alexandre Jourdon, David Juan, Sattar Khoshkhoo, Sonia Kim, Huira C Kopera, Kenneth Y Kwan, Minseok Kwon, Ben Langmead, Eunjung Alice Lee, Sara Linker, Irene Lobon, Michael A Lodato, Lovelace J Luquette, Gary Mathern, Tomas Marques-Bonet, Eduardo A Maury, Michael Miller, Manuel Solis Moruno, Rujuta Narurkar, Apua Paquola, Reenal Pattni, Raquel Garcia Perez, Inna Povolotskaya, Patrick Reed, Rachel Rodin, Chaggai Rosenbluh, Soraya Scuderi, Maxwell Sherman, Richard Straub, Eduardo Soriano, Chen Sun, Jeremy Thorpe, Vinay Viswanadham, Meiyan Wang, Xuefang Zhao, Bo Zhou, Weichen Zhou, Zinan Zhou, Xiaowei Zhu

Affiliations

¹ Program in Biochemistry, Molecular and Cellular Biology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
² Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
³ Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06520, USA.
⁴ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
⁵ Child Study Center, Yale University, New Haven, CT, 06520, USA.
⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁷ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁸ Sage Bionetworks, 2901 Third Ave., Suite 330, Seattle, WA, 98121, USA.
⁹ Lieber Institute for Brain Development, Baltimore, MD, 21205, USA.
¹⁰ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹¹ Rady Children's Institute for Genomic Medicine, 7910 Frost St., Suite #300, San Diego, CA, 92123, USA.
¹² Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
¹³ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Icahn Institute for Data Science and Genomic Technologies, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Laboratory of Genetics LOG-G, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
¹⁶ Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA.
¹⁷ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA.
¹⁸ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, 94305, USA.
²⁰ Department of Genetics, Stanford University School of Medicine, Stanford, California, 94305, USA.
²¹ Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.
²² Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
²³ McKusick Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁴ Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁵ Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁶ National Human Genome Research Institute, National Institutes of Health, 6700B Rockledge Dr, Bethesda, MD, 20892, USA.
²⁷ Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA. Abyzov.Alexej@mayo.edu.

PMID: 37985666
PMCID: PMC10662356
DOI: 10.1038/s41597-023-02645-7

Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases

McKinzie A Garrison et al. Sci Data. 2023.

. 2023 Nov 20;10(1):813.

doi: 10.1038/s41597-023-02645-7.

Authors

Collaborators

BSMN Consortium:
Aitor Serres Amero, Danny Antaki, Dan Averbuj, Laurel Ball, Sara Bizzotto, Craig Bohrson, Rebeca Borges-Monroy, Martin Breuss, Sean Cho, Chong Chu, Changuk Chung, Isidro Cortes-Ciriano, Michael Coulter, Kenneth Daily, Caroline Dias, Alissa D'Gama, Yanmei Dou, Jennifer Erwin, Diane A Flasch, Trenton J Frisbie, Alon Galor, Javier Ganz, Doga Gulhan, Robert Hill, August Yue Huang, Andrew Jaffe, Alexandre Jourdon, David Juan, Sattar Khoshkhoo, Sonia Kim, Huira C Kopera, Kenneth Y Kwan, Minseok Kwon, Ben Langmead, Eunjung Alice Lee, Sara Linker, Irene Lobon, Michael A Lodato, Lovelace J Luquette, Gary Mathern, Tomas Marques-Bonet, Eduardo A Maury, Michael Miller, Manuel Solis Moruno, Rujuta Narurkar, Apua Paquola, Reenal Pattni, Raquel Garcia Perez, Inna Povolotskaya, Patrick Reed, Rachel Rodin, Chaggai Rosenbluh, Soraya Scuderi, Maxwell Sherman, Richard Straub, Eduardo Soriano, Chen Sun, Jeremy Thorpe, Vinay Viswanadham, Meiyan Wang, Xuefang Zhao, Bo Zhou, Weichen Zhou, Zinan Zhou, Xiaowei Zhu

Affiliations

¹ Program in Biochemistry, Molecular and Cellular Biology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
² Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
³ Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06520, USA.
⁴ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
⁵ Child Study Center, Yale University, New Haven, CT, 06520, USA.
⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁷ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁸ Sage Bionetworks, 2901 Third Ave., Suite 330, Seattle, WA, 98121, USA.
⁹ Lieber Institute for Brain Development, Baltimore, MD, 21205, USA.
¹⁰ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹¹ Rady Children's Institute for Genomic Medicine, 7910 Frost St., Suite #300, San Diego, CA, 92123, USA.
¹² Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
¹³ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Icahn Institute for Data Science and Genomic Technologies, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Laboratory of Genetics LOG-G, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
¹⁶ Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA.
¹⁷ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA.
¹⁸ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, 94305, USA.
²⁰ Department of Genetics, Stanford University School of Medicine, Stanford, California, 94305, USA.
²¹ Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.
²² Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
²³ McKusick Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁴ Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁵ Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁶ National Human Genome Research Institute, National Institutes of Health, 6700B Rockledge Dr, Bethesda, MD, 20892, USA.
²⁷ Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA. Abyzov.Alexej@mayo.edu.

PMID: 37985666
PMCID: PMC10662356
DOI: 10.1038/s41597-023-02645-7

Abstract

Somatic mosaicism is defined as an occurrence of two or more populations of cells having genomic sequences differing at given loci in an individual who is derived from a single zygote. It is a characteristic of multicellular organisms that plays a crucial role in normal development and disease. To study the nature and extent of somatic mosaicism in autism spectrum disorder, bipolar disorder, focal cortical dysplasia, schizophrenia, and Tourette syndrome, a multi-institutional consortium called the Brain Somatic Mosaicism Network (BSMN) was formed through the National Institute of Mental Health (NIMH). In addition to genomic data of affected and neurotypical brains, the BSMN also developed and validated a best practices somatic single nucleotide variant calling workflow through the analysis of reference brain tissue. These resources, which include >400 terabytes of data from 1087 subjects, are now available to the research community via the NIMH Data Archive (NDA) and are described here.

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Conflict of interest statement

JVM is an inventor on patent US6150160, is a paid consultant for Gilead Sciences, and serves on the scientific advisory board of Tessera Therapeutics Inc., where he is paid as a consultant and has equity options. He has also recently served on the American Society of Human Genetics Board of Directors. CAW is a paid consultant to Third Rock Ventures and Flagship Pioneering, and is on the Clinical Advisory Board of Maze Therapeutics. DRW is on the Scientific Advisory Boards of Sage Therapeutics and Pasithea Therapeutics. The other authors do not declare competing interests. This article was prepared while MAP was employed at Sage Bionetworks. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institute on Aging, the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Figures

**Fig. 1**
Heterozygous and homozygous (a) SNP and (b) indel counts in targeted exonic regions. Data represents uniformly processed WES data of cohorts from the University of San Diego (NDA ID 2968), University of Michigan (NDA ID 2966), and Kennedy Krieger Institute (KKI; NDA ID 2964). Phenotype for each cohort is marked at the bottom of the figure in a rugchart.

**Fig. 2**
Heterozygous and homozygous (a) SNP and (b) indel counts in the uniformly processed WGS data in the cohorts from Mount Sinai School of Medicine (MSSM; NDA ID 2965), University of San Diego (UCSD; NDA ID 2968), Yale University (NDA ID 2961), Harvard University (NDA ID 2962), and the Lieber Institute for Brain Development (LIBD; NDA ID 2967). Phenotype is marked at the bottom in a rugchart. Some samples with possible contamination are labeled.

**Fig. 3**
Variant allele frequencies (VAFs) for heterozygous SNPs were obtained for each sample using GATK HaplotypeCaller with ploidy 2. Two example distributions are shown here for samples LIBD01 and LIBD104 (collection 2967). The distribution is shifted from 50% and does not appear normally distributed for LIBD104 suggesting contamination of the sequenced sample with unrelated DNA.

**Fig. 4**
Ratios of heterozygous and homozygous indels to SNPs across all cohorts for all uniformly processed WGS data.

**Fig. 5**
Quality of RNA-seq data. (a) Postmortem interval (PMI) of affected (n = 38) and control (n = 42) individuals in the two Yale cohorts (collections 2960 and 2961), which were the only cohorts with such a data type. Differences were not statistically significant (p > 0.05). (b) RIN values of ASD-affected (n = 63 ASD, n = 23 suspected ASD samples) and control (n = 73 neurotypical control samples) RNA-seq samples from Yale cohort 2960.

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References

1. Jourdon A, Fasching L, Scuderi S, Abyzov A, Vaccarino FM. The role of somatic mosaicism in brain disease. Curr. Opin. Genet. Dev. 2020;65:84–90. doi: 10.1016/j.gde.2020.05.002. - DOI - PMC - PubMed
1. D’Gama AM, Walsh CA. Somatic mosaicism and neurodevelopmental disease. Nat. Neurosci. 2018;21:1504–1518. doi: 10.1038/s41593-018-0257-3. - DOI - PubMed
1. McConnell MJ, et al. Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. Science. 2017;356:eaal1641. doi: 10.1126/science.aal1641. - DOI - PMC - PubMed
1. Rodin RE, Walsh CA. Somatic mutation in pediatric neurological diseases. Pediatr. Neurol. 2018;87:20–22. doi: 10.1016/j.pediatrneurol.2018.08.008. - DOI - PMC - PubMed
1. Rodin RE, et al. The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing. Nat. Neurosci. 2021;24:176–185. doi: 10.1038/s41593-020-00765-6. - DOI - PMC - PubMed

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Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases

Collaborators

Affiliations

Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical