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[Preprint]. 2024 Sep 8:2024.09.06.611689.

doi: 10.1101/2024.09.06.611689.

A blended genome and exome sequencing method captures genetic variation in an unbiased, high-quality, and cost-effective manner

Toni A Boltz^{1

2}, Benjamin B Chu³, Calwing Liao^{1

2

4}, Julia M Sealock^{1

2

4}, Robert Ye^{1

2

4}, Lerato Majara^{1

2

5}, Jack M Fu^{4

6}, Susan Service⁷, Lingyu Zhan^{8

9}, Sarah E Medland¹⁰, Sinéad B Chapman^{1

2

4

11}, Simone Rubinacci^{4

12

13}, Matthew DeFelice¹⁴, Jonna L Grimsby¹⁴, Tamrat Abebe¹⁵, Melkam Alemayehu³, Fred K Ashaba¹⁶, Elizabeth G Atkinson^{17

18}, Tim Bigdeli¹⁹, Amanda B Bradway¹⁴, Harrison Brand^{4

20}, Lori B Chibnik^{1

21

22}, Abebaw Fekadu^{3

23}, Michael Gatzen¹⁴, Bizu Gelaye^{1

22

24}, Stella Gichuru²⁵, Marissa L Gildea¹⁴, Toni C Hill¹⁴, Hailiang Huang^{1

2

4

11}, Kalyn M Hubbard¹⁴, Wilfred E Injera²⁶, Roxanne James²⁷, Moses Joloba²⁸, Christopher Kachulis¹⁴, Phillip R Kalmbach¹⁴, Rogers Kamulegeya²⁸, Gabriel Kigen²⁹, Soyeon Kim^{1

2

4}, Nastassja Koen^{27

30}, Edith K Kwobah²⁵, Joseph Kyebuzibwa³¹, Seungmo Lee³², Niall J Lennon¹⁴, Penelope A Lind¹⁰, Esteban A Lopera-Maya^{7

33}, Johnstone Makale³⁴, Serghei Mangul^{35

36}, Justin McMahon^{1

22}, Pierre Mowlem³⁷, Henry Musinguzi¹⁶, Rehema M Mwema³⁸, Noeline Nakasujja³¹, Carter P Newman^{1

22}, Lethukuthula L Nkambule^{1

2}, Conor R O'Neil¹⁴, Ana Maria Olivares¹, Catherine M Olsen¹⁰, Linnet Ongeri³⁹, Sophie J Parsa^{1

2}, Adele Pretorius²⁷, Raj Ramesar³⁰, Faye L Reagan¹⁴, Chiara Sabatti⁴⁰, Jacquelyn A Schneider¹⁴, Welelta Shiferaw³, Anne Stevenson^{1

22

41}, Erik Stricker¹⁷, Rocky E Stroud 2nd^{1

22}, Jessie Tang¹⁴, David Whiteman¹⁰, Mary T Yohannes^{1

2}, Mingrui Yu^{1

2

4}, Kai Yuan^{1

2

4}; NeuroGAP-Psychosis; Dickens Akena³¹, Lukoye Atwoli^{42

43

44}, Symon M Kariuki^{45

46}, Karestan C Koenen^{1

22

47

48}, Charles R J C Newton^{38

46}, Dan J Stein³⁰, Solomon Teferra³, Zukiswa Zingela⁴⁹, Carlos N Pato^{50

11}, Michele T Pato^{50

11}, Carlos Lopez-Jaramillo⁵¹, Nelson Freimer^{11

7

33}, Roel A Ophoff^{7

33}, Loes M Olde Loohuis^{7

33

52}, Michael E Talkowski^{1

4

20}, Benjamin M Neale^{1

2

4

11}, Daniel P Howrigan^{1

2

4}, Alicia R Martin^{1

2

4

11}

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Psychiatry and Mental Health and South African Medical Council Research Unit on Risk and Resilience in Mental Disorders, Neuroscience Institute, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
⁶ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Department of Psychiatry, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
⁹ The Collaboratory, Institute for Quantitative and Computational Biosciences, University of California Los Angeles, Los Angeles, CA, USA.
¹⁰ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹¹ BD2: Breakthrough Discoveries for thriving with Bipolar Disorder, Santa Monica, CA, USA.
¹² Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School,, Boston, MA, USA.
¹³ Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School,, Boston, MA, USA.
¹⁴ Broad Clinical Labs (BCL), Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Department of Microbiology, Immunology, and Parasitology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
¹⁶ Department of Immunology & Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda.
¹⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
¹⁸ Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
¹⁹ Institute for Genomics in Health, The State University of New York, Brooklyn, NY, USA.
²⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²¹ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
²² Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
²³ Centre for Innovative Drug Development & Therapeutic Trials for Africa, Addis Ababa University, Addis Ababa, Ethiopia.
²⁴ Department of Psychiatry, Harvard Medical School and The Chester M. Pierce MD, Division of Global Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Department of Mental Health, Moi Teaching and Referral Hospital, Eldoret, Kenya.
²⁶ Department of Medical Laboratory Sciences, School of Health Sciences, Alupe University, Busia, Kenya.
²⁷ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
²⁸ School of Biomedical Sciences, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
²⁹ Department of Pharmacology and Toxicology, Moi University School of Medicine, Eldoret, Kenya.
³⁰ SA MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town and Neuroscience Institute, Cape Town, South Africa.
³¹ Department of Psychiatry, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
³² Department of Computer Science, University of California Los Angeles, Los Angeles, CA, USA.
³³ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³⁴ Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya.
³⁵ Department of Quantitative and Computational Biology, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA.
³⁶ Department of Clinical Pharmacy, Alfred E. Mann School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
³⁷ Ampath Laboratories, Moi University School of Medicine, Eldoret, Kenya.
³⁸ Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast,, Kilifi, Kenya.
³⁹ Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
⁴⁰ Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
⁴¹ Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
⁴² Department of Mental Health and Behavioural Sciences, School of Medicine, Moi University College of Health Sciences, Eldoret, Kenya.
⁴³ Brain and Mind Institute, The Aga Khan University, Nairobi, Kenya.
⁴⁴ Department of Medicine, Medical College East Africa, The Aga Khan University, Nairobi, Kenya.
⁴⁵ Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya.
⁴⁶ Department of Psychiatry, University of Oxford, Oxford, UK.
⁴⁷ Department of Social and Behavioral Sciences, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
⁴⁸ Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁴⁹ Executive Dean's Office, Faculty of Health Sciences, Nelson Mandela University, Gqebera, South Africa.
⁵⁰ Rutgers University, New Brunswick, NJ, USA.
⁵¹ Department of Psychiatry, University of Antioquia, University of Antioquia, Medellín, Antioquia, Colombia.
⁵² Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

PMID: 39282356
PMCID: PMC11398523
DOI: 10.1101/2024.09.06.611689

A blended genome and exome sequencing method captures genetic variation in an unbiased, high-quality, and cost-effective manner

Toni A Boltz et al. bioRxiv. 2024.

[Preprint]. 2024 Sep 8:2024.09.06.611689.

doi: 10.1101/2024.09.06.611689.

Authors

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Psychiatry and Mental Health and South African Medical Council Research Unit on Risk and Resilience in Mental Disorders, Neuroscience Institute, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
⁶ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Department of Psychiatry, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
⁹ The Collaboratory, Institute for Quantitative and Computational Biosciences, University of California Los Angeles, Los Angeles, CA, USA.
¹⁰ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹¹ BD2: Breakthrough Discoveries for thriving with Bipolar Disorder, Santa Monica, CA, USA.
¹² Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School,, Boston, MA, USA.
¹³ Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School,, Boston, MA, USA.
¹⁴ Broad Clinical Labs (BCL), Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Department of Microbiology, Immunology, and Parasitology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
¹⁶ Department of Immunology & Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda.
¹⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
¹⁸ Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
¹⁹ Institute for Genomics in Health, The State University of New York, Brooklyn, NY, USA.
²⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²¹ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
²² Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
²³ Centre for Innovative Drug Development & Therapeutic Trials for Africa, Addis Ababa University, Addis Ababa, Ethiopia.
²⁴ Department of Psychiatry, Harvard Medical School and The Chester M. Pierce MD, Division of Global Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Department of Mental Health, Moi Teaching and Referral Hospital, Eldoret, Kenya.
²⁶ Department of Medical Laboratory Sciences, School of Health Sciences, Alupe University, Busia, Kenya.
²⁷ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
²⁸ School of Biomedical Sciences, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
²⁹ Department of Pharmacology and Toxicology, Moi University School of Medicine, Eldoret, Kenya.
³⁰ SA MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town and Neuroscience Institute, Cape Town, South Africa.
³¹ Department of Psychiatry, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
³² Department of Computer Science, University of California Los Angeles, Los Angeles, CA, USA.
³³ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³⁴ Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya.
³⁵ Department of Quantitative and Computational Biology, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA.
³⁶ Department of Clinical Pharmacy, Alfred E. Mann School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
³⁷ Ampath Laboratories, Moi University School of Medicine, Eldoret, Kenya.
³⁸ Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast,, Kilifi, Kenya.
³⁹ Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
⁴⁰ Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
⁴¹ Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
⁴² Department of Mental Health and Behavioural Sciences, School of Medicine, Moi University College of Health Sciences, Eldoret, Kenya.
⁴³ Brain and Mind Institute, The Aga Khan University, Nairobi, Kenya.
⁴⁴ Department of Medicine, Medical College East Africa, The Aga Khan University, Nairobi, Kenya.
⁴⁵ Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya.
⁴⁶ Department of Psychiatry, University of Oxford, Oxford, UK.
⁴⁷ Department of Social and Behavioral Sciences, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
⁴⁸ Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁴⁹ Executive Dean's Office, Faculty of Health Sciences, Nelson Mandela University, Gqebera, South Africa.
⁵⁰ Rutgers University, New Brunswick, NJ, USA.
⁵¹ Department of Psychiatry, University of Antioquia, University of Antioquia, Medellín, Antioquia, Colombia.
⁵² Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

PMID: 39282356
PMCID: PMC11398523
DOI: 10.1101/2024.09.06.611689

Abstract

We deployed the Blended Genome Exome (BGE), a DNA library blending approach that generates low pass whole genome (1-4× mean depth) and deep whole exome (30-40× mean depth) data in a single sequencing run. This technology is cost-effective, empowers most genomic discoveries possible with deep whole genome sequencing, and provides an unbiased method to capture the diversity of common SNP variation across the globe. To evaluate this new technology at scale, we applied BGE to sequence >53,000 samples from the Populations Underrepresented in Mental Illness Associations Studies (PUMAS) Project, which included participants across African, African American, and Latin American populations. We evaluated the accuracy of BGE imputed genotypes against raw genotype calls from the Illumina Global Screening Array. All PUMAS cohorts had $R^{2}$ concordance ≥95% among SNPs with MAF≥1%, and never fell below ≥90% $R^{2}$ for SNPs with MAF<1%. Furthermore, concordance rates among local ancestries within two recently admixed cohorts were consistent among SNPs with MAF≥1%, with only minor deviations in SNPs with MAF<1%. We also benchmarked the discovery capacity of BGE to access protein-coding copy number variants (CNVs) against deep whole genome data, finding that deletions and duplications spanning at least 3 exons had a positive predicted value of ~90%. Our results demonstrate BGE scalability and efficacy in capturing SNPs, indels, and CNVs in the human genome at 28% of the cost of deep whole-genome sequencing. BGE is poised to enhance access to genomic testing and empower genomic discoveries, particularly in underrepresented populations.

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Figures

**Figure 1.. Expected ancestral diversity, coverage, and quality from BGE data at scale.**
A) Principal components (PC) 1 vs PC2 and B) PC3 vs PC4, C) Fraction of exome target covered with at least 10x depth stratified by cohort and collection method. Solid lines indicate saliva collection (NeuroGAP) and dashed lines indicate blood collection (GPC and Paisa). D) Estimated mean WGS coverage, mean coding depth, mean coding call rate and mean coding genotype quality.

**Figure 2.. Protein-coding copy number variants have expected qualities with BGE compared to WGS.**
A) Recall and positive predictive value (PPV) of CNVs called from the BGE relative to matched WGS samples (N=400). B) Distribution of deletions and duplications across all cohorts. C) Distribution of CNV sizes across cohorts by number of exons. D) Proportion of unique deletion and duplication carriers across cohorts. E) Comparison of CNV size across cohorts by number of exons for saliva and blood. F) Comparison of unique deletion and duplication carriers between blood and saliva.

**Figure 3:. Imputation of BGE data is highly concordant with GWAS array data across MAF bins.**
The sizes of points correspond to numbers of SNPs in each MAF bin. Variants are filtered to those passing an INFO score >= 0.8. SNP MAFs are defined within cohorts using the GSA array for the Paisa and GPC cohorts. Due to limited GSA samples in the NeuroGAP cohorts, MAFs are defined using the HGDP+1kGP AFR subset.

**Figure 4.. Imputation accuracy differentiates by local ancestry background at low allele frequencies.**
A) Aggregate $R^{2}$ in the Paisa cohort. B) Aggregate $R^{2}$ in the GPC cohort. Note # genotypes legend stands for number of genotypes, with one value for each sample and each SNP. Heterozygous ancestry results with non-reference concordance measurements are in Supplementary Figure 5.

See this image and copyright information in PMC

References

1. Visscher P. M. et al. 10 Years of GWAS Discovery: Biology, Function, and Translation. Am. J. Hum. Genet. 101, 5–22 (2017). - PMC - PubMed
1. Pasaniuc B. et al. Extremely low-coverage sequencing and imputation increases power for genome-wide association studies. Nat. Genet. 44, 631–635 (2012). - PMC - PubMed
1. Martin A. R. et al. Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations. Am. J. Hum. Genet. 108, 656–668 (2021). - PMC - PubMed
1. Plenge R. M., Scolnick E. M. & Altshuler D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013). - PubMed
1. Minikel E. V. et al. Evaluating drug targets through human loss-of-function genetic variation. Nature 581, 459–464 (2020). - PMC - PubMed

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This is a preprint.

A blended genome and exome sequencing method captures genetic variation in an unbiased, high-quality, and cost-effective manner

Affiliations

A blended genome and exome sequencing method captures genetic variation in an unbiased, high-quality, and cost-effective manner

Authors

Affiliations

Abstract

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References

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