Whole genome sequencing in psychiatric disorders: the WGSPD consortium

Stephan J Sanders¹, Benjamin M Neale^{2

3}, Hailiang Huang^{2

3}, Donna M Werling¹, Joon-Yong An¹, Shan Dong¹; Whole Genome Sequencing for Psychiatric Disorders (WGSPD); Goncalo Abecasis⁴, P Alexander Arguello⁵, John Blangero⁶, Michael Boehnke⁴, Mark J Daly^{2

3}, Kevin Eggan³, Daniel H Geschwind^{7

8}, David C Glahn⁹, David B Goldstein¹⁰, Raquel E Gur¹¹, Robert E Handsaker³, Steven A McCarroll³, Roel A Ophoff^{12

13

14}, Aarno Palotie³, Carlos N Pato¹⁵, Chiara Sabatti¹⁶, Matthew W State¹, A Jeremy Willsey¹, Steven E Hyman¹⁷, Anjene M Addington¹⁸, Thomas Lehner¹⁹, Nelson B Freimer²⁰

Affiliations

¹ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁵ National Institute of Mental Health, Bethesda, MD, USA.
⁶ South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, School of Medicine, Brownsville, TX, USA.
⁷ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
¹⁰ Institute for Genomic Medicine, Columbia University Medical Center, Hammer Health Sciences, New York, NY, USA.
¹¹ Department of Psychiatry, Neuropsychiatry Section, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹² Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
¹³ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹⁵ Department of Psychiatry, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁶ Department of Health Research and Policy, Division of Biostatistics, Stanford University, Stanford, CA, USA.
¹⁷ Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. seh@harvard.edu.
¹⁸ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA. anjene.addington@nih.gov.
¹⁹ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA. tlehner@mail.nih.gov.
²⁰ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA. nfreimer@mednet.ucla.edu.

PMID: 29184211
PMCID: PMC7785336
DOI: 10.1038/s41593-017-0017-9

Review

Whole genome sequencing in psychiatric disorders: the WGSPD consortium

Stephan J Sanders et al. Nat Neurosci. 2017 Dec.

. 2017 Dec;20(12):1661-1668.

doi: 10.1038/s41593-017-0017-9.

Authors

Affiliations

¹ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁵ National Institute of Mental Health, Bethesda, MD, USA.
⁶ South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, School of Medicine, Brownsville, TX, USA.
⁷ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
¹⁰ Institute for Genomic Medicine, Columbia University Medical Center, Hammer Health Sciences, New York, NY, USA.
¹¹ Department of Psychiatry, Neuropsychiatry Section, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹² Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
¹³ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹⁵ Department of Psychiatry, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁶ Department of Health Research and Policy, Division of Biostatistics, Stanford University, Stanford, CA, USA.
¹⁷ Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. seh@harvard.edu.
¹⁸ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA. anjene.addington@nih.gov.
¹⁹ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA. tlehner@mail.nih.gov.
²⁰ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA. nfreimer@mednet.ucla.edu.

PMID: 29184211
PMCID: PMC7785336
DOI: 10.1038/s41593-017-0017-9

Erratum in

Publisher Correction: Whole genome sequencing in psychiatric disorders: the WGSPD consortium.
Sanders SJ, Neale BM, Huang H, Werling DM, An JY, Dong S, Abecasis G, Arguello PA, Blangero J, Boehnke M, Daly MJ, Eggan K, Geschwind DH, Glahn DC, Goldstein DB, Gur RE, Handsaker RE, McCarroll SA, Ophoff RA, Palotie A, Pato CN, Sabatti C, State MW, Willsey AJ, Hyman SE, Addington AM, Lehner T, Freimer NB; Whole Genome Sequencing for Psychiatric Disorders (WGSPD). Sanders SJ, et al. Nat Neurosci. 2018 Jul;21(7):1017. doi: 10.1038/s41593-018-0102-8. Nat Neurosci. 2018. PMID: 29549319

Abstract

As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.

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Figures

**Figure 1.. Statistical power in the noncoding genome.**
We estimated the power at a significance threshold (alpha) of 5 × 10⁻⁵, selected to account for 1,000 categories of noncoding variants, to detect an excess of noncoding variants at 122,500 risk loci in cases vs. controls as we varied the relative risk and risk:non-risk ratio, which represents annotation quality (Table S2). In a) we assessed the power for detecting an excess of de novo mutations in 5,000 cases vs. 5,000 controls as the relative risk increases. With a risk:non-risk ratio of 1:20, approximately equivalent to assessing protein truncating variants in the coding genome, we achieve >80% power with a relative risk of 5. In b) the power to detect an excess burden of rare variants (allele frequency ≤0.1%) is assessed in 20,000 cases vs. 20,000 controls. In c) we assessed the power to identify an excess of de novo mutations at a specific genomic locus, e.g. the noncoding region regulating a single gene. Consequently, we set the significance threshold (alpha) at 2.5×10⁻⁶. In d) we assessed the power to identify an excess of rare variants (allele frequency ≤0.1%) at a specific nucleotide (alpha = 1.7×10⁻¹¹), since this yielded better power than testing for burden at a locus (alpha = 2.5×10⁻⁶).

See this image and copyright information in PMC

References

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1. Sanders SJ First glimpses of the neurobiology of autism spectrum disorder. Curr. Opin. Genet. Dev. (2015). doi:10.1016/j.gde.2015.10.002 - DOI - PubMed

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Whole genome sequencing in psychiatric disorders: the WGSPD consortium

Affiliations

Whole genome sequencing in psychiatric disorders: the WGSPD consortium

Authors

Affiliations

Erratum in

Abstract

Figures

References

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

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