Genome-wide association study of down syndrome-associated atrioventricular septal defects

Dhanya Ramachandran, Zhen Zeng, Adam E. Locke, Jennifer G. Mulle, Lora J H Bean, Tracie C. Rosser, Kenneth J. Dooley, Clifford L. Cua, George T. Capone, Roger H. Reeves, Cheryl Maslen, David J. Cutler, Eleanor Feingold, Stephanie L. Sherman, Michael E. Zwick

    Research output: Contribution to journalArticle

    12 Citations (Scopus)

    Abstract

    The goal of this study was to identify the contribution of common genetic variants to Down syndrome2associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome2associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.

    Original languageEnglish (US)
    Pages (from-to)1961-1971
    Number of pages11
    JournalG3: Genes, Genomes, Genetics
    Volume5
    Issue number10
    DOIs
    StatePublished - 2015

    Fingerprint

    Genome-Wide Association Study
    Down Syndrome
    Chromosomes, Human, Pair 21
    Congenital Heart Defects
    Population
    Logistic Models
    Odds Ratio
    Regression Analysis
    Genome
    Atrioventricular Septal Defect
    Genes

    Keywords

    • Aneuploidy
    • Birth defect
    • Complex trait
    • Congenital heart defect
    • Trisomy

    ASJC Scopus subject areas

    • Genetics
    • Molecular Biology
    • Genetics(clinical)

    Cite this

    Ramachandran, D., Zeng, Z., Locke, A. E., Mulle, J. G., Bean, L. J. H., Rosser, T. C., ... Zwick, M. E. (2015). Genome-wide association study of down syndrome-associated atrioventricular septal defects. G3: Genes, Genomes, Genetics, 5(10), 1961-1971. https://doi.org/10.1534/g3.115.019943

    Genome-wide association study of down syndrome-associated atrioventricular septal defects. / Ramachandran, Dhanya; Zeng, Zhen; Locke, Adam E.; Mulle, Jennifer G.; Bean, Lora J H; Rosser, Tracie C.; Dooley, Kenneth J.; Cua, Clifford L.; Capone, George T.; Reeves, Roger H.; Maslen, Cheryl; Cutler, David J.; Feingold, Eleanor; Sherman, Stephanie L.; Zwick, Michael E.

    In: G3: Genes, Genomes, Genetics, Vol. 5, No. 10, 2015, p. 1961-1971.

    Research output: Contribution to journalArticle

    Ramachandran, D, Zeng, Z, Locke, AE, Mulle, JG, Bean, LJH, Rosser, TC, Dooley, KJ, Cua, CL, Capone, GT, Reeves, RH, Maslen, C, Cutler, DJ, Feingold, E, Sherman, SL & Zwick, ME 2015, 'Genome-wide association study of down syndrome-associated atrioventricular septal defects', G3: Genes, Genomes, Genetics, vol. 5, no. 10, pp. 1961-1971. https://doi.org/10.1534/g3.115.019943
    Ramachandran, Dhanya ; Zeng, Zhen ; Locke, Adam E. ; Mulle, Jennifer G. ; Bean, Lora J H ; Rosser, Tracie C. ; Dooley, Kenneth J. ; Cua, Clifford L. ; Capone, George T. ; Reeves, Roger H. ; Maslen, Cheryl ; Cutler, David J. ; Feingold, Eleanor ; Sherman, Stephanie L. ; Zwick, Michael E. / Genome-wide association study of down syndrome-associated atrioventricular septal defects. In: G3: Genes, Genomes, Genetics. 2015 ; Vol. 5, No. 10. pp. 1961-1971.
    @article{3152e7e7bb7749fa92de373d476c5ea6,
    title = "Genome-wide association study of down syndrome-associated atrioventricular septal defects",
    abstract = "The goal of this study was to identify the contribution of common genetic variants to Down syndrome2associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome2associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.",
    keywords = "Aneuploidy, Birth defect, Complex trait, Congenital heart defect, Trisomy",
    author = "Dhanya Ramachandran and Zhen Zeng and Locke, {Adam E.} and Mulle, {Jennifer G.} and Bean, {Lora J H} and Rosser, {Tracie C.} and Dooley, {Kenneth J.} and Cua, {Clifford L.} and Capone, {George T.} and Reeves, {Roger H.} and Cheryl Maslen and Cutler, {David J.} and Eleanor Feingold and Sherman, {Stephanie L.} and Zwick, {Michael E.}",
    year = "2015",
    doi = "10.1534/g3.115.019943",
    language = "English (US)",
    volume = "5",
    pages = "1961--1971",
    journal = "G3: Genes, Genomes, Genetics",
    issn = "2160-1836",
    publisher = "Genetics Society of America",
    number = "10",

    }

    TY - JOUR

    T1 - Genome-wide association study of down syndrome-associated atrioventricular septal defects

    AU - Ramachandran, Dhanya

    AU - Zeng, Zhen

    AU - Locke, Adam E.

    AU - Mulle, Jennifer G.

    AU - Bean, Lora J H

    AU - Rosser, Tracie C.

    AU - Dooley, Kenneth J.

    AU - Cua, Clifford L.

    AU - Capone, George T.

    AU - Reeves, Roger H.

    AU - Maslen, Cheryl

    AU - Cutler, David J.

    AU - Feingold, Eleanor

    AU - Sherman, Stephanie L.

    AU - Zwick, Michael E.

    PY - 2015

    Y1 - 2015

    N2 - The goal of this study was to identify the contribution of common genetic variants to Down syndrome2associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome2associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.

    AB - The goal of this study was to identify the contribution of common genetic variants to Down syndrome2associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome2associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.

    KW - Aneuploidy

    KW - Birth defect

    KW - Complex trait

    KW - Congenital heart defect

    KW - Trisomy

    UR - http://www.scopus.com/inward/record.url?scp=84943422903&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84943422903&partnerID=8YFLogxK

    U2 - 10.1534/g3.115.019943

    DO - 10.1534/g3.115.019943

    M3 - Article

    VL - 5

    SP - 1961

    EP - 1971

    JO - G3: Genes, Genomes, Genetics

    JF - G3: Genes, Genomes, Genetics

    SN - 2160-1836

    IS - 10

    ER -