Genetic association analysis with FAMHAP: a major program update

Herold, Christine; Becker, Tim

doi:10.1093/bioinformatics/btn581

Cited by 59 publications

(81 citation statements)

References 10 publications

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“…This splice isoform corresponds to the previously described STX1A isoform STX1C. 15 In order to confirm absent or low STX1A mRNA expression in nasal epithelium, we performed splice-isoform-specific qPCR of STX1A and STX1C, revealing that STX1C mRNA is 4350 times higher expressed than STX1A. Similar results were obtained in all epithelia investigated, with STX1C being at least 50 times higher expressed than STX1A (Figure 2).…”

Section: Influence Of Stx1a/c Variants On Clinical Outcomesupporting

confidence: 81%

“…In the European Sib and Twin Study cohort, genetic data of the association study were evaluated using the FAMHAP software package, which accepts data evaluation in association studies on unrelated individuals as well as on affected sib pairs. 15 The raw observed P values (P raw ) were corrected for multiple testing by haplotype permutation (P global ). 16 …”

Section: Statisticsmentioning

confidence: 99%

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Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

et al. 2013

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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR). Disease severity in CF varies greatly, and sibling studies strongly indicate that genes other than CFTR modify disease outcome. Syntaxin 1A (STX1A) has been reported as a negative regulator of CFTR and other ion channels. We hypothesized that STX1A variants act as a CF modifier by influencing the remaining function of mutated CFTR. We identified STX1A variants by genomic resequencing patients from the Bernese CF Patient Data Registry and applied linear mixed model analysis to establish genotype-phenotype correlations, revealing STX1A rs4363087 (c.467 À38A4G) to significantly influence lung function. The same STX1A risk allele was recognized in the European CF Twin and Sibling Study (P ¼ 0.0027), demonstrating that the genotype-phenotype association of STX1A to CF disease severity is robust enough to allow replication in two independent CF populations. rs4363087 is in linkage disequilibrium to the exonic variant rs2228607 (c.204C4T). Considering that neither rs4363087 nor rs2228607 changes the amino-acid sequence of STX1A, we investigated their effects on mRNA level. We show that rs2228607 reinforces aberrant splicing of STX1A mRNA, leading to nonsense-mediated mRNA decay. In conclusion, we demonstrate the clinical relevance of STX1A variants in CF, and evidence the functional relevance of STX1A variant rs2228607 at molecular level. Our findings show that genes interacting with CFTR can modify CF disease progression.

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Section: Influence Of Stx1a/c Variants On Clinical Outcomesupporting

confidence: 81%

Section: Statisticsmentioning

confidence: 99%

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

et al. 2013

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“…An advantage of the HAP-2 approach is that a fast implementation is part of the FAMHAP software update for GWAS. 72 The haplotype cluster approach performed only slightly better than the two-marker approaches in explicit haplotype disease models (M3 and M4). It is not unlikely that the relative performance of the haplotype cluster approach would have been better in the presence of haplotype models with more than two independent disease markers.…”

Section: Joint Analysis Of Tightly Linked Snps In Gwas T Becker and Cmentioning

confidence: 93%

Joint analysis of tightly linked SNPs in screening step of genome-wide association studies leads to increased power

Becker

Herold

2009

Eur J Hum Genet

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Recent developments in genome-wide association studies (GWAS) have lead to the localization of disease genes for many complex diseases. The scrutiny of the respective publications reveals, first, that statistical analysis is restricted typically to single-marker analysis in the first step, and that, second, the presence of multiple, independently associated SNPs within the same linkage disequilibrium (LD) region is a common phenomenon. Motivated by this observation, we show through a power simulation study that a simultaneous analysis of tightly linked SNPs in the initial GWAS analysis step would lead to increased power, when compared with that in single-marker analysis. This is true for all the three approaches we considered (implementations in BEAGLE, FAMHAP and UNPHASED). The best performance was obtained using a two-marker haplotype analysis. In conclusion, we would expect additional gene findings for re-analyzing successful GWAS with a multi-marker approach. European Journal of Human Genetics (2009Genetics ( ) 17, 1043Genetics ( -1049 doi:10.1038/ejhg.2009 published online 18 February 2009 Keywords: genome-wide association studies; haplotypes; literature study Introduction Biology strongly supports the potential importance of haplotype analysis in genetic association studies. 1 Major reasons for haplotype analysis are possible representations of non-genotyped SNPs and the presence of multiple, independent disease markers in the same linkage disequilibrium (LD) region. 2 Nevertheless, evidence that haplotypes actually lead to improved power in genetic association studies has yet to be supplied. Indeed, the increased number of degrees of freedom (d.f.) might over-compensate the benefit achieved from the improved modeling of biology obtainable with haplotypes. Besides that, it is not self-evident whether haplotype assignment is actually a prerequisite for association analysis in LD regions. Clayton et al 3 suggest, as an alternative, the analysis of unphased multi-marker genotype data in these regions.In view of the controversial situation regarding the judgement of haplotype analysis, we conducted a largescale power simulation study for investigating the relative performance of single-marker analysis, simultaneous analysis of unphased genotypes in LD regions -referred to as UMMA (unphased multi-marker analysis) from now onand haplotype analysis in genome-wide association studies (GWAS). The setup of the simulation study was guided by a priori knowledge that has become recently available. Data from the International HapMap Project 4 allowed specifying empirical LD distributions for data simulation. In addition, we extracted information on disease models typical of complex diseases, by studying a comprehensive list of recent publications on GWAS. Results of literature studyThe guidelines for inclusion into the literature study were publication during the time period from January 2005 to 5 -42,44 -64 which met our inclusion criteria. In all publications, association analysis in the initial step was restrict...

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“…Genetic data for the association study was evaluated using the FAMHAP software package, 35 which allows family-based analysis 36,37 and accepts data evaluation in association studies on unrelated individuals, as well as on affected sib pairs. 35 All case-reference comparisons were carried out using 10 000 Monte-Carlo simulated data sets.…”

Section: Association Studymentioning

confidence: 99%

“…35 All case-reference comparisons were carried out using 10 000 Monte-Carlo simulated data sets. [35][36][37] Nuclear families were analyzed by the transmission-disequilibrium test 38 extended to both nuclear families with more than one affected child and to multimarker haplotypes. [35][36][37] The analysis of more than one marker per locus is corrected for multiple testing by haplotype permutation (P global ).…”

Section: Association Studymentioning

confidence: 99%

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

et al. 2011

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We have used a stepwise approach consisting of initial interrogation, confirmation and fine mapping to analyze STAT3, IL1B and IFNGR1 as modifiers of cystic fibrosis disease building upon the data and sample collection of the European Cystic Fibrosis Twin and Sibling Study. We have observed direct correlation between the length of the intronic microsatellite STAT3Sat to STAT3 expression levels among F508del-CFTR homozygous patients (P¼0.0075), and an association of longer STAT3Sat-alleles with the presence of CFTR-mediated residual chloride secretion (P¼0.0031), measured as the manifestation of the CF basic defect in intestinal tissue. Both, family-based analysis by TDT and case-reference comparison identified consistently the same intragenic IL1B haplotype as a risk variant (P raw ¼0.055 for TDT, P raw o0.3 for case-reference comparison). Using haplotypeguided hierarchical fine mapping, we have identified two single nucleotide exchanges for which concordant and discordant sibling pairs differ at a 7 kb -spanning core haplotype in IFNGR1 (P raw ¼0.0113). Taken together, our findings imply that immunorelevant pathways and ion secretion, dominated by CFTR in intestinal and respiratory epithelium, merge at the level of the epithelial cell to integrate the signaling of cytokines due to innate and acquired immune defense.

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Genetic association analysis with FAMHAP: a major program update

Abstract: The software is available at http://famhap.meb.uni-bonn.de

Cited by 59 publications

References 10 publications

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

Joint analysis of tightly linked SNPs in screening step of genome-wide association studies leads to increased power

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

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