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The methods for genome scan linkage analysis of qualitative and quantitative COPD-related phenotypes
are described in the following manuscripts:
Silverman EK, Mosley J, Palmer LJ, Barth M, Senter JM, Brown A, Drazen JM,
Kwiatkowski DJ, Chapman HA, Campbell EJ, Province MA, Rao DC, Reilly JJ, Ginns LC, Speizer FE, Weiss ST.
Genome-wide
linkage analysis of severe, early-onset chronic
obstructive pulmonary disease: Airflow obstruction and chronic bronchitis phenotypes.
Hum Molec Genet 2002; 11:623-632.
Silverman EK, Palmer LJ, Mosley JD, Barth M, Senter JM, Brown A, Drazen JM,
Kwiatkowski DJ, Chapman HA, Campbell EJ, Province MA, Rao DC, Reilly JJ, Ginns LC,
Speizer FE, Weiss ST.
Genome-wide
Linkage Analysis of Quantitative Spirometric
Phenotypes in Severe, Early-Onset Chronic Obstructive Pulmonary Disease.
Am J Hum Genet 2002; 70:1229-1239.
Briefly, 585 subjects from 72 severe, early-onset COPD pedigrees were included in
the linkage analyses. 378 Short Tandem Repeat (STR) markers were genotyped by the
NHLBI Mammalian Genotyping Service. This data set was used for both the qualitative
and quantitative phenotype genome scan analyses.
For the qualitative COPD-related phenotypes (HMG Paper), nonparametric linkage analysis
was performed using ALLEGRO for three qualitative phenotypes: moderate airflow obstruction
(FEV1 < 60% predicted with FEV1/FVC < 90% predicted), mild airflow obstruction
(FEV1 < 80% predicted with FEV1/FVC < 90% predicted), and chronic bronchitis.
Output from the ALLEGRO program are presented on this web site, for all subjects and for
smokers only (phenotype data missing for subjects with < 10 pack-years of smoking).
The exponential model with the Score=All option was used. Please note that the distances
presented in the ALLEGRO output are relative to the first marker used, not the end of the chromosome.
For example, the first STR marker on chromosome 12 is actually 6 cM from the end of the short arm of chromosome
12; thus, the actual genetic distances correspond to the distance reported by ALLEGRO plus 6 cM.
On chromosome 12, twelve additional STR markers were genotyped at the Channing Laboratory. These
markers are referred to by D-number, with abbreviations such as referring to D12S1303 as d1303.
The chromosome 12 flanking marker results are presented using a nonparametric multipoint approach
with ALLEGRO, a parametric multipoint approach with ALLEGRO (assuming a dominant model with
penetrance 0.5 and no phenocopies), and two point linkage analysis with one dominant and one
recessive model (Maximized Maximum Lod Score approach).
For the quantitative COPD-related phenotypes (AJHG Paper), variance component linkage analysis was
performed using SOLAR for three quantitative phenotypes: FEV1, FEV1/FVC, and FVC. Covariates were
included for age, height, race, gender, pack-years of smoking, and quadratic terms (where appropriate).
The genetic distances from SOLAR are presented relative to the end of the short arm of the chromosome.
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