Dataset Information

Genetic analysis in young-age-of-onset Graves' disease reveals new susceptibility loci.

ABSTRACT: Genetic and environmental factors play an essential role in the pathogenesis of Graves' Disease (GD). Children with GD have less exposure time to environmental factors and therefore are believed to harbor stronger genetic susceptibility than adults.The aim of the study was to identify susceptibility loci that predispose to GD in patients with young-age-of-onset (YAO) GD.One hundred six patients with YAO GD (onset <30 y) and 855 healthy subjects were studied. Cases and controls were genotyped using the Illumina Infinium Immunochip, designed to genotype 196,524 polymorphisms. Case control association analyses were performed using the PLINK computer package. Ingenuity Pathway Analysis program (QIAGEN) was used to carry out pathway analyses.Immunochip genetic association analysis identified 30 single-nucleotide polymorphisms in several genes that were significantly associated with YAO GD, including major histocompatibility complex class I and class II genes, BTNL2, NOTCH4, TNFAIP3, and CXCR4. Candidate gene analysis revealed that most of the genes previously shown to be associated with adult-onset GD were also associated with YAO GD. Pathway analysis demonstrated that antigen presentation, T-helper cell differentiation, and B cell development were the major pathways contributing to the pathogenesis of YAO GD.Genetic analysis identified novel susceptibility loci in YAO GD adding a new dimension to the understanding of GD etiology.

SUBMITTER: Brown RS

PROVIDER: S-EPMC4079314 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Genetic analysis in young-age-of-onset Graves' disease reveals new susceptibility loci.

Brown Rosalind S RS Lombardi Angela A Hasham Alia A Greenberg David A DA Gordon Joshua J Concepcion Erlinda E Hammerstad Sara S SS Lotay Vaneet V Zhang Weijia W Tomer Yaron Y

The Journal of clinical endocrinology and metabolism 20140331 7

<h4>Context</h4>Genetic and environmental factors play an essential role in the pathogenesis of Graves' Disease (GD). Children with GD have less exposure time to environmental factors and therefore are believed to harbor stronger genetic susceptibility than adults.<h4>Objective</h4>The aim of the study was to identify susceptibility loci that predispose to GD in patients with young-age-of-onset (YAO) GD.<h4>Setting and design</h4>One hundred six patients with YAO GD (onset <30 y) and 855 healthy ...[more]

PMID: 24684463

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Project description:IMPORTANCE:Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES:To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS:The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES:Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS:Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P <?.005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242). CONCLUSIONS AND RELEVANCE:We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Dataset Information

Genetic analysis in young-age-of-onset Graves' disease reveals new susceptibility loci.

Publications

Genetic analysis in young-age-of-onset Graves' disease reveals new susceptibility loci.

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