TY - JOUR
T1 - Finding Missing Heritability in Less Significant Loci and Allelic Heterogeneity
T2 - Genetic Variation in Human Height
AU - Zhang, Ge
AU - Karns, Rebekah
AU - Sun, Guangyun
AU - Indugula, Subba Rao
AU - Cheng, Hong
AU - Havas-Augustin, Dubravka
AU - Novokmet, Natalija
AU - Durakovic, Zijad
AU - Missoni, Sasa
AU - Chakraborty, Ranajit
AU - Rudan, Pavao
AU - Deka, Ranjan
PY - 2012/12/12
Y1 - 2012/12/12
N2 - Genome-wide association studies (GWAS) have identified many common variants associated with complex traits in human populations. Thus far, most reported variants have relatively small effects and explain only a small proportion of phenotypic variance, leading to the issues of 'missing' heritability and its explanation. Using height as an example, we examined two possible sources of missing heritability: first, variants with smaller effects whose associations with height failed to reach genome-wide significance and second, allelic heterogeneity due to the effects of multiple variants at a single locus. Using a novel analytical approach we examined allelic heterogeneity of height-associated loci selected from SNPs of different significance levels based on the summary data of the GIANT (stage 1) studies. In a sample of 1,304 individuals collected from an island population of the Adriatic coast of Croatia, we assessed the extent of height variance explained by incorporating the effects of less significant height loci and multiple effective SNPs at the same loci. Our results indicate that approximately half of the 118 loci that achieved stringent genome-wide significance (p-value<5×10-8) showed evidence of allelic heterogeneity. Additionally, including less significant loci (i.e., p-value<5×10-4) and accounting for effects of allelic heterogeneity substantially improved the variance explained in height.
AB - Genome-wide association studies (GWAS) have identified many common variants associated with complex traits in human populations. Thus far, most reported variants have relatively small effects and explain only a small proportion of phenotypic variance, leading to the issues of 'missing' heritability and its explanation. Using height as an example, we examined two possible sources of missing heritability: first, variants with smaller effects whose associations with height failed to reach genome-wide significance and second, allelic heterogeneity due to the effects of multiple variants at a single locus. Using a novel analytical approach we examined allelic heterogeneity of height-associated loci selected from SNPs of different significance levels based on the summary data of the GIANT (stage 1) studies. In a sample of 1,304 individuals collected from an island population of the Adriatic coast of Croatia, we assessed the extent of height variance explained by incorporating the effects of less significant height loci and multiple effective SNPs at the same loci. Our results indicate that approximately half of the 118 loci that achieved stringent genome-wide significance (p-value<5×10-8) showed evidence of allelic heterogeneity. Additionally, including less significant loci (i.e., p-value<5×10-4) and accounting for effects of allelic heterogeneity substantially improved the variance explained in height.
UR - http://www.scopus.com/inward/record.url?scp=84871250165&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0051211
DO - 10.1371/journal.pone.0051211
M3 - Article
C2 - 23251454
AN - SCOPUS:84871250165
SN - 1932-6203
VL - 7
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - e51211
ER -