Heterogeneity of marker allele frequencies hinders interpretation of linkage analysis: illustration on chromosome 18 markers.
In the first part of our study we tested linkage with chromosome 18 markers in a sample of bipolar I sib pairs. We did not obtain evidence for linkage but showed that we could not exclude the presence of a disease locus (having even a non-negligible effect). The limitation of the sib-pair sample size, and consequently of the conclusions, was a result of our care in assuring that the linkage analysis was free of possible errors in the marker allele frequencies. In the second part, we illustrated the possible impact of such heterogeneity in a single data set when applying the multipoint (APM) method. An Amish pedigree included in the study of Berrettini et al. was analyzed under two sets of marker allele frequencies. One set corresponds to estimates from the entire data set and the second to estimates from the Amish pedigree only. Very different values for the APM statistics were obtained. Although the real frequencies are unknown for this family belonging to an isolated population, this example illustrates that heterogeneity in the populations from which familial data are collected may artificially increase evidence for linkage and hinder interpretation of the analysis.
Margaritte-Jeannin
P
P
Genetic Epidemiology Research Unit, INSERM U155, Paris, France.
Babron
M C
MC
Génin
E
E
Eichenbaum-Voline
S
S
Clerget-Darpoux
F
F
D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18; D003627:Data Interpretation, Statistical; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D016555:Matched-Pair Analysis; D009679:Nuclear Family; D010375:Pedigree
D005819:Genetic Markers