Abstract
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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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).
Conflict of interest
Drs. Yang, Han, and Gelernter report no competing interests. Dr. Kranzler reports consulting arrangements with Lundbeck, GlaxoSmithKline, Gilead, and Alkermes and research support from Merck ACTIVE). Dr. Kranzler also reports associations with Eli Lilly, Janssen, Schering Plough, Lundbeck, Alkermes, GlaxoSmithKline, Abbott, and Johnson & Johnson, as these companies provide support to the ACNP Alcohol Clinical Trials Initiative (ACTIVE) and Dr. Kranzler receives support from ACTIVE.
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Supplementary Fig. 1 The histograms of admixture proportion (African ancestry) for each subset of families that show increased evidence for linkage (PDF 332 kb)
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Han, S., Gelernter, J., Kranzler, H.R. et al. Ordered subset linkage analysis based on admixture proportion identifies new linkage evidence for alcohol dependence in African-Americans. Hum Genet 132, 397–403 (2013). https://doi.org/10.1007/s00439-012-1255-2
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DOI: https://doi.org/10.1007/s00439-012-1255-2