A genome-wide search for linkage to allergic rhinitis in Danish sib-pair families

Abstract

Allergic rhinitis (AR) is a complex disorder with a polygenic, multifactorial aetiology. Twin studies have found the genetic contribution to be substantial. We collected and clinically characterised a sample consisting of 127 Danish nuclear families with at least two siblings suffering from AR or allergic conjunctivitis including 540 individuals (286 children and 254 parents). A whole-genome linkage scan, using 424 microsatellite markers, was performed on both this sample and an earlier collected sample consisting of 130 families with atopic dermatitis and other atopic disorders. A third sib-pair family sample, which was previously collected and genotyped, was added to the analysis increasing the total sample size to 357 families consisting of 1508 individuals. In total, 190 families with AR was included. The linkage analysis software Genehunter NPL, Genehunter MOD, and Genehunter Imprinting were used to obtain nonparametric and parametric linkage results. Family-based association analysis of positional candidate SNPs was carried out using the FBAT program. We obtained genome-wide significant linkage to a novel AR locus at 1p13 and suggestive linkage to two novel regions at 1q31-q32 and 20p12, respectively. Family-based association analysis of SNPs in the candidate locus DNND1B/CRB1 at 1q31 showed no significant association and could not explain the linkage signal observed. Suggestive evidence of linkage was also obtained at three AR loci previously reported (2q14-q23, 2q23, and 12p13) and indication of linkage was observed at a number of additional loci. Likely maternal imprinting was observed at 2q23, and possible maternal imprinting at 3q28.

Properties and Evaluation of the MOBIT – a novel Linkage-based Test Statistic and Quantification Method for Imprinting

“…Our group has implemented the MOD score approach, including a routine to perform simulations under the null hypothesis of no linkage, in the GENEHUNTER-MODSCORE (GHM) software (Brugger & Strauch, 2014;Dietter et al, 2007;Mattheisen et al, 2008;Strauch, 2003), which is based on the GENEHUNTER program (Kruglyak et al, 1996). Its application has led to the identification of a variety of genetic disease loci responsible for congenital heart defects (Flaquer et al, 2013), allergic rhinitis (Kruse et al, 2012), atopic dermatitis (Christensen et al, 2009), bipolar affective disorder (Schumacher et al, 2005), and house dust mite allergy (Kurz et al, 2005). Nonparametric linkage methods have been proposed as an alternative to parametric analysis.…”

Genetics of Allergic Diseases

“…Similarly, multiple linkage studies were performed for AD (summarized in Ref . 24 ) and AR 25–29 . It was frequently observed that loci overlapped across associated traits; for example, Daniels and colleagues observed overlapping linkage peaks with quantitative traits associated with asthma including total serum IgE, skin test index, and eosinophil counts, as well as atopy as a qualitative trait 8 .…”

Fast Linkage Analysis with MOD Scores Using Algebraic Calculation

“…Our group has implemented the MOD-score approach, including a routine to perform simulations under the null hypothesis, in the GENEHUNTER-MODSCORE (GHM) software [10][11][12][13] . Its application has led to the identification of a variety of genetic disease loci [14][15][16][17][18] .…”