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Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.

ABSTRACT: Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.

SUBMITTER: Flannick J

PROVIDER: S-EPMC4051627 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.

Flannick Jason J Beer Nicola L NL Bick Alexander G AG Agarwala Vineeta V Molnes Janne J Gupta Namrata N Burtt Noël P NP Florez Jose C JC Meigs James B JB Taylor Herman H Lyssenko Valeriya V Irgens Henrik H Fox Ervin E Burslem Frank F Johansson Stefan S Brosnan M Julia MJ Trimmer Jeff K JK Newton-Cheh Christopher C Tuomi Tiinamaija T Molven Anders A Wilson James G JG O'Donnell Christopher J CJ Kathiresan Sekar S Hirschhorn Joel N JN Njølstad Pål R PR Rolph Tim T Seidman J G JG Gabriel Stacey S Cox David R DR Seidman Christine E CE Groop Leif L Altshuler David D

Nature genetics 20131006 11

Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according t ...[more]

PMID: 24097065

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Project description:The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.

Dataset Information

Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.

Publications

Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.

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