TY - JOUR
T1 - Ordered subset linkage analysis based on admixture proportion identifies new linkage evidence for alcohol dependence in African-Americans
AU - Han, Shizhong
AU - Gelernter, Joel
AU - Kranzler, Henry R.
AU - Yang, Bao Zhu
N1 - Funding Information:
Acknowledgments The authors are grateful to the volunteer families and individuals who participated in this research study. This work was supported by the U.S. National Institutes of Health (R01 AA11330, R01 AA017535, K24AA013736, R01 DA12849, R01 DA12690, R01 DA018432, R01DA030976, K01 DA024758, and M01 RR06192) and by the US Department of Veterans Affairs (VA CT REAP and New England MIRECC Center; VA CT Alcohol Research Center). It was also partially supported by the Alcoholic Beverage Medical Research Foundation Grant (SH).
PY - 2013/4
Y1 - 2013/4
N2 - Genetic heterogeneity could reduce the power of linkage analysis to detect risk loci for complex traits such as alcohol dependence (AD). Previously, we performed a genomewide linkage analysis for AD in African-Americans (AAs) (Biol Psychiatry 65:111-115, 2009). The power of that linkage analysis could have been reduced by the presence of genetic heterogeneity owing to differences in admixture among AA families. We hypothesized that by examining a study sample whose genetic ancestry was more homogeneous, we could increase the power to detect linkage. To test this hypothesis, we performed ordered subset linkage analysis in 384 AA families using admixture proportion as a covariate to identify a more homogeneous subset of families and determine whether there is increased evidence for linkage with AD. Statistically significant increases in lod scores in subsets relative to the overall sample were identified on chromosomes 4 (P = 0.0001), 12 (P = 0.021), 15 (P = 0.026) and 22 (P = 0.0069). In a subset of 44 families with African ancestry proportions ranging from 0.858 to 0.996, we observed a genomewide significant linkage at 180 cM on chromosome 4 (lod = 4.24, pointwise P < 0.00001, empirical genomewide P = 0.008). A promising candidate gene located there, GLRA3, which encodes a subunit of the glycine neurotransmitter receptor. Our results demonstrate that admixture proportion can be used as a covariate to reduce genetic heterogeneity and enhance the detection of linkage for AD in an admixed population such as AAs. This approach could be applied to any linkage analysis for complex traits conducted in an admixed population.
AB - Genetic heterogeneity could reduce the power of linkage analysis to detect risk loci for complex traits such as alcohol dependence (AD). Previously, we performed a genomewide linkage analysis for AD in African-Americans (AAs) (Biol Psychiatry 65:111-115, 2009). The power of that linkage analysis could have been reduced by the presence of genetic heterogeneity owing to differences in admixture among AA families. We hypothesized that by examining a study sample whose genetic ancestry was more homogeneous, we could increase the power to detect linkage. To test this hypothesis, we performed ordered subset linkage analysis in 384 AA families using admixture proportion as a covariate to identify a more homogeneous subset of families and determine whether there is increased evidence for linkage with AD. Statistically significant increases in lod scores in subsets relative to the overall sample were identified on chromosomes 4 (P = 0.0001), 12 (P = 0.021), 15 (P = 0.026) and 22 (P = 0.0069). In a subset of 44 families with African ancestry proportions ranging from 0.858 to 0.996, we observed a genomewide significant linkage at 180 cM on chromosome 4 (lod = 4.24, pointwise P < 0.00001, empirical genomewide P = 0.008). A promising candidate gene located there, GLRA3, which encodes a subunit of the glycine neurotransmitter receptor. Our results demonstrate that admixture proportion can be used as a covariate to reduce genetic heterogeneity and enhance the detection of linkage for AD in an admixed population such as AAs. This approach could be applied to any linkage analysis for complex traits conducted in an admixed population.
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U2 - 10.1007/s00439-012-1255-2
DO - 10.1007/s00439-012-1255-2
M3 - Article
C2 - 23239122
AN - SCOPUS:84876468508
SN - 0340-6717
VL - 132
SP - 397
EP - 403
JO - Human genetics
JF - Human genetics
IS - 4
ER -