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Protocol publication

[…] lumina CytoSNP-12 arrays and QC was done as described elsewhere (). The GoNL panel was used for imputation of LLS and VlaVla and was done as described elsewhere (). The final dataset included 11,177 participants of LLS and 1,394 of VlaVla., In work all individuals were genotyped using the Illumina HumanExome arrays (v1.1 and v1.2; Illumina, San Diego, CA, United States). For more information please refer to their publication ()., For the genome-wide linkage analysis, 142 related COPD cases from ERF were used. The cases were linked in a single large pedigree of 23 generations. However, due to the linkage software restraints, the cases were clustered into 27 smaller (≤24 bits) families using PEDCUT software (). We used HaploPainter () to illustrate all 27 pedigrees (Supplementary Figure ). We then performed affected-only parametric linkage analysis in MERLIN software () using incomplete penetrance and no phenocopies for both dominant (0, 0.5, 0.5) and recessive models (0, 0, 0.5) (). The measure of the likelihood of linkage is the LOD score and we considered LOD ≥ 3.3 to be statistically significant. Further we performed per-family analysis for significant regions to identify the families with COPD cases contributing the most to the LOD score., Next, we used exome-sequence data in ERF to identify rare variants that may explain the identified linkage peaks. For this, among all variants in this region we selected only variants with predicted damaging effects on protein (missense and stop-coding) based on the FunctionGVS column of the SeattleSeq Annotation database from the National Heart, Lung and Blood Institute (NHLBI) and with MAF < 0.05 in the general population (1000 Genomes). As frequencies in a genetically isolated population may be inflated or deflated due to genetic drift (), we used the MAF from the general population for filtering. We selected variants shared among most (>50%) of the affected family members as candidate variants., A formal test of association was performed for the identified candidate variants in each study – ERF, in samples with exome-sequence (N = 636) and in exome-chip (N = 572) data, in three RS cohorts (RS-I, RS-II, and RS-III), using the HRC imputed data (N = 11,372), the LLS (N = […]

Pipeline specifications

Software tools PedCut, HaploPainter, Merlin, SeattleSeq Annotation
Chemicals Amino Acids, Pyridines, Nicotinic Acids, Pyridines, Nicotinic Acids