Within-family outliers: segregating alleles or environmental effects? A linkage analysis of height from 5815 sibling pairs.
Most information in linkage analysis for quantitative traits comes from pairs of relatives that are phenotypically most discordant or concordant. Confounding this, within-family outliers from non-genetic causes may create false positives and negatives. We investigated the influence of within-family outliers empirically, using one of the largest genome-wide linkage scans for height. The subjects were drawn from Australian twin cohorts consisting of 8447 individuals in 2861 families, providing a total of 5815 possible pairs of siblings in sibships. A variance component linkage analysis was performed, either including or excluding the within-family outliers. Using the entire dataset, the largest LOD scores were on chromosome 15q (LOD 2.3) and 11q (1.5). Excluding within-family outliers increased the LOD score for most regions, but the LOD score on chromosome 15 decreased from 2.3 to 1.2, suggesting that the outliers may create false negatives and false positives, although rare alleles of large effect may also be an explanation. Several regions suggestive of linkage to height were found after removing the outliers, including 1q23.1 (2.0), 3q22.1 (1.9) and 5q32 (2.3). We conclude that the investigation of the effect of within-family outliers, which is usually neglected, should be a standard quality control measure in linkage analysis for complex traits and may reduce the noise for the search of common variants of modest effect size as well as help identify rare variants of large effect and clinical significance. We suggest that the effect of within-family outliers deserves further investigation via theoretical and simulation studies.
Benyamin
Beben
B
Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia. bebenB@qimr.edu.au
Perola
Markus
M
Cornes
Belinda K
BK
Madden
Pamela Af
PA
Palotie
Aarno
A
Nyholt
Dale R
DR
Montgomery
Grant W
GW
Peltonen
Leena
L
Martin
Nicholas G
NG
Visscher
Peter M
PM
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001827:Body Height / Q000235:genetics*; D002874:Chromosome Mapping; D002877:Chromosomes, Human; D004777:Environment; D005260:Female; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D040641:Quantitative Trait Loci; D035781:Siblings; D014427:Twins