Although genetic studies have been spectacularly successful in detecting genes responsible for singlelocus Mendelian disorders, a multitude of problems plague genetic studies of complex disorders. Loci of small effect, genetic and ethnic heterogeneity, and missing parental and founder genotypes decrease power and increase rates of false positives. A wide variety of analytic techniques are available, each with its own separate hypotheses and literature. Unfortunately, power for these methods is often tested with normally distributed traits, genetically homogeneous populations, large effect loci, and fully informative pedigrees. Real complex disorders rarely meet these conditions; this may lead to overly optimistic beliefs about the ability to localize genes for complex disorders and subsequent disappointment when putative disease loci fail to replicate in other samples. Correcting for non-normal distributions and mixed ethnicities may increase power and reduce false positives The overall theme of this proposal is robust linkage analysis. In particular, the hypotheses underlying linkage studies and the potential for performing corrections for data that violates these hypotheses will be examined over the course of the mentored career development award. The training will focus on developing an understanding of psychiatric nosology through didactic coursework, patient presentations, and formal and informal lectures. These training goals are designed to provide the psychiatric, genetic, and statistical skills necessary to understand the hypotheses underlying linkage studies of psychiatric disorders and to determine how to measure and adjust phenotypes, genetic marker data, and computation. The research goals of this proposal are to perform a set of simulation studies to develop and evaluate novel methods of analyzing ordinal data and non-normally distributed data, to adjust for mixed and rare ethnicities in linkage methods, and to adapt linkage studies to an association framework. Once developed, these methods will be applied to data from the Collaborative Study of the Genetics of Alcoholism (COGA). Novel, genetically relevant phenotypes will be derived from the COGA data using experience gained from the training component. Additionally, a publicly accessible online archive will be created to freely provide simulated data and software developed during this award.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AA015572-02
Application #
7252660
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Zha, Wenxing
Project Start
2006-07-01
Project End
2011-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$125,607
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Bloom, A Joseph; Murphy, Sharon E; Martinez, Maribel et al. (2013) Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption. Pharmacogenet Genomics 23:62-8
Bloom, A Joseph; Harari, Oscar; Martinez, Maribel et al. (2013) A compensatory effect upon splicing results in normal function of the CYP2A6*14 allele. Pharmacogenet Genomics 23:107-16
Hinrichs, Anthony L; Murphy, Sharon E; Wang, Jen C et al. (2011) Common polymorphisms in FMO1 are associated with nicotine dependence. Pharmacogenet Genomics 21:397-402
Hinrichs, Anthony L; Suarez, Brian K (2011) Incorporating linkage information into a common disease/rare variant framework. Genet Epidemiol 35 Suppl 1:S74-9
Bloom, Joseph; Hinrichs, Anthony L; Wang, Jen C et al. (2011) The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans. Pharmacogenet Genomics 21:403-16
Hinrichs, Anthony L; Mintun, Mark A; Head, Denise et al. (2010) Cortical binding of pittsburgh compound B, an endophenotype for genetic studies of Alzheimer's disease. Biol Psychiatry 67:581-3
Saccone, Nancy L; Saccone, Scott F; Hinrichs, Anthony L et al. (2009) Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet 150B:453-66
Saccone, Nancy L; Wang, Jen C; Breslau, Naomi et al. (2009) The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer Res 69:6848-56
Hinrichs, Anthony L; Culverhouse, Robert; Jin, Carol H et al. (2009) Detecting population stratification using related individuals. BMC Proc 3 Suppl 7:S106
Hinrichs, Anthony L; Larkin, Emma K; Suarez, Brian K (2009) Population stratification and patterns of linkage disequilibrium. Genet Epidemiol 33 Suppl 1:S88-92

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