publication . Article . Preprint . Other literature type . 2018

A reference haplotype panel for genome-wide imputation of short tandem repeats

Shubham Saini; Ileena Mitra; Nima Mousavi; Stephanie Feupe Fotsing; Melissa Gymrek;
Open Access
  • Published: 23 Oct 2018
  • Publisher: eScholarship, University of California
  • Country: Algeria
Abstract
Short tandem repeats (STRs) are involved in dozens of Mendelian disorders and have been implicated in complex traits. However, genotyping arrays used in genome-wide association studies focus on single nucleotide polymorphisms (SNPs) and do not readily allow identification of STR associations. We leverage next-generation sequencing (NGS) from 479 families to create a SNP + STR reference haplotype panel. Our panel enables imputing STR genotypes into SNP array data when NGS is not available for directly genotyping STRs. Imputed genotypes achieve mean concordance of 97% with observed genotypes in an external dataset compared to 71% expected under a naive model. Perf...
Subjects
Medical Subject Headings: humanities
free text keywords: Humans, Microsatellite Repeats, Haplotypes, Polymorphism, Single Nucleotide, Alleles, Genome, Human, Reference Standards, Genetic Variation, Article, Science, Q, General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry
Funded by
NIH| Systematic identification and interpretation of repetitive variants underlying schizophrenia
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1DP5OD024577-01
  • Funding stream: OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH
,
NIH| Expanding the accessible genetic architecture of autism by single molecule sequencing
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01MH113715-02
  • Funding stream: NATIONAL INSTITUTE OF MENTAL HEALTH
Communities
Digital Humanities and Cultural Heritage
73 references, page 1 of 5

1.Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

Scott, RA. An expanded genome-wide association study of type 2 diabetes in Europeans. Diabetes. 2017; 66: 2888-2902 [OpenAIRE] [PubMed] [DOI]

Turcot, V. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat. Genet.. 2018; 50: 26-41 [OpenAIRE] [PubMed] [DOI]

Marchini, J, Howie, B. Genotype imputation for genome-wide association studies. Nat. Rev. Genet.. 2010; 11: 499-511 [OpenAIRE] [PubMed] [DOI]

5.Yengo, L. et al. Meta-analysis of genome-wide association studies for height and body mass index in ~700,000 individuals of European ancestry. Preprint at https://www.biorxiv.org/content/early/2018/03/22/274654 (2018).

Sekar, A. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530: 177-183 [OpenAIRE] [PubMed] [DOI]

Boettger, LM. Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels. Nat. Genet.. 2016; 48: 359-366 [OpenAIRE] [PubMed] [DOI]

8.Leffler, E. M. et al. Resistance to malaria through structural variation of red blood cell invasion receptors. Science 356, 6343 (2017).

Lander, ES. Initial sequencing and analysis of the human genome. Nature. 2001; 409: 860-921 [OpenAIRE] [PubMed] [DOI]

Hannan, AJ. Tandem repeat polymorphisms: modulators of disease susceptibility and candidates for ‘missing heritability’. Trends Genet.. 2010; 26: 59-65 [OpenAIRE] [PubMed] [DOI]

Hannan, AJ. Tandem repeats mediating genetic plasticity in health and disease. Nat. Rev. Genet.. 2018; 19: 286-298 [OpenAIRE] [PubMed] [DOI]

Press, MO, Carlson, KD, Queitsch, C. The overdue promise of short tandem repeat variation for heritability. Trends Genet.. 2014; 30: 504-512 [OpenAIRE] [PubMed] [DOI]

Sun, JX. A direct characterization of human mutation based on microsatellites. Nat. Genet.. 2012; 44: 1161-1165 [OpenAIRE] [PubMed] [DOI]

Willems, T, Gymrek, M, Highnam, G, Genomes Project, C, Mittelman, D, Erlich, Y. The landscape of human STR variation. Genome Res.. 2014; 24: 1894-1904 [OpenAIRE] [PubMed] [DOI]

Acuna-Hidalgo, R, Veltman, JA, Hoischen, A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol.. 2016; 17: 241 [OpenAIRE] [PubMed] [DOI]

73 references, page 1 of 5
Abstract
Short tandem repeats (STRs) are involved in dozens of Mendelian disorders and have been implicated in complex traits. However, genotyping arrays used in genome-wide association studies focus on single nucleotide polymorphisms (SNPs) and do not readily allow identification of STR associations. We leverage next-generation sequencing (NGS) from 479 families to create a SNP + STR reference haplotype panel. Our panel enables imputing STR genotypes into SNP array data when NGS is not available for directly genotyping STRs. Imputed genotypes achieve mean concordance of 97% with observed genotypes in an external dataset compared to 71% expected under a naive model. Perf...
Subjects
Medical Subject Headings: humanities
free text keywords: Humans, Microsatellite Repeats, Haplotypes, Polymorphism, Single Nucleotide, Alleles, Genome, Human, Reference Standards, Genetic Variation, Article, Science, Q, General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry
Funded by
NIH| Systematic identification and interpretation of repetitive variants underlying schizophrenia
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1DP5OD024577-01
  • Funding stream: OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH
,
NIH| Expanding the accessible genetic architecture of autism by single molecule sequencing
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01MH113715-02
  • Funding stream: NATIONAL INSTITUTE OF MENTAL HEALTH
Communities
Digital Humanities and Cultural Heritage
73 references, page 1 of 5

1.Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

Scott, RA. An expanded genome-wide association study of type 2 diabetes in Europeans. Diabetes. 2017; 66: 2888-2902 [OpenAIRE] [PubMed] [DOI]

Turcot, V. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat. Genet.. 2018; 50: 26-41 [OpenAIRE] [PubMed] [DOI]

Marchini, J, Howie, B. Genotype imputation for genome-wide association studies. Nat. Rev. Genet.. 2010; 11: 499-511 [OpenAIRE] [PubMed] [DOI]

5.Yengo, L. et al. Meta-analysis of genome-wide association studies for height and body mass index in ~700,000 individuals of European ancestry. Preprint at https://www.biorxiv.org/content/early/2018/03/22/274654 (2018).

Sekar, A. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530: 177-183 [OpenAIRE] [PubMed] [DOI]

Boettger, LM. Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels. Nat. Genet.. 2016; 48: 359-366 [OpenAIRE] [PubMed] [DOI]

8.Leffler, E. M. et al. Resistance to malaria through structural variation of red blood cell invasion receptors. Science 356, 6343 (2017).

Lander, ES. Initial sequencing and analysis of the human genome. Nature. 2001; 409: 860-921 [OpenAIRE] [PubMed] [DOI]

Hannan, AJ. Tandem repeat polymorphisms: modulators of disease susceptibility and candidates for ‘missing heritability’. Trends Genet.. 2010; 26: 59-65 [OpenAIRE] [PubMed] [DOI]

Hannan, AJ. Tandem repeats mediating genetic plasticity in health and disease. Nat. Rev. Genet.. 2018; 19: 286-298 [OpenAIRE] [PubMed] [DOI]

Press, MO, Carlson, KD, Queitsch, C. The overdue promise of short tandem repeat variation for heritability. Trends Genet.. 2014; 30: 504-512 [OpenAIRE] [PubMed] [DOI]

Sun, JX. A direct characterization of human mutation based on microsatellites. Nat. Genet.. 2012; 44: 1161-1165 [OpenAIRE] [PubMed] [DOI]

Willems, T, Gymrek, M, Highnam, G, Genomes Project, C, Mittelman, D, Erlich, Y. The landscape of human STR variation. Genome Res.. 2014; 24: 1894-1904 [OpenAIRE] [PubMed] [DOI]

Acuna-Hidalgo, R, Veltman, JA, Hoischen, A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol.. 2016; 17: 241 [OpenAIRE] [PubMed] [DOI]

73 references, page 1 of 5
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