Human Genetics

, Volume 132, Issue 4, pp 397–403

Ordered subset linkage analysis based on admixture proportion identifies new linkage evidence for alcohol dependence in African-Americans

  • Shizhong Han
  • Joel Gelernter
  • Henry R. Kranzler
  • Bao-Zhu Yang
Original Investigation

DOI: 10.1007/s00439-012-1255-2

Cite this article as:
Han, S., Gelernter, J., Kranzler, H.R. et al. Hum Genet (2013) 132: 397. doi:10.1007/s00439-012-1255-2


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.

Supplementary material

439_2012_1255_MOESM1_ESM.doc (32 kb)
Supplementary material 1 (DOC 32 kb)
439_2012_1255_MOESM2_ESM.pdf (333 kb)
Supplementary Fig. 1 The histograms of admixture proportion (African ancestry) for each subset of families that show increased evidence for linkage (PDF 332 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Shizhong Han
    • 1
    • 2
  • Joel Gelernter
    • 1
    • 3
  • Henry R. Kranzler
    • 4
    • 5
  • Bao-Zhu Yang
    • 1
  1. 1.Department of PsychiatryYale University School of Medicine, New Haven, Connecticut and VA CT Healthcare Center 116A2West HavenUSA
  2. 2.Department of PsychiatryUniversity of Iowa Carver College of MedicineIowa CityUSA
  3. 3.Departments of Genetics and of NeurobiologyYale University School of MedicineNew HavenUSA
  4. 4.Department of PsychiatryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  5. 5.VISN 4 MIRECCPhiladelphia VAMCPhiladelphiaUSA

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