Bivariate quantitative trait linkage analysis: Pleiotropy versus coincident linkage

Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
Genetic Epidemiology (Impact Factor: 2.6). 01/1997; 14(6):953 - 958. DOI: 10.1002/(SICI)1098-2272(1997)14:6<953::AID-GEPI65>3.0.CO;2-K

ABSTRACT Power to detect linkage and localization of a major gene were compared in univariate and bivariate variance components linkage analysis of three related quantitative traits in general pedigrees. Although both methods demonstrated adequate power to detect loci of moderate effect, bivariate analysis improved both power and localization for correlated quantitative traits mapping to the same chromosomal region, regardless of whether co-localization was the result of pleiotropy. Additionally, a test of pleiotropy versus co-incident linkage was shown to have adequate power and a low error rate. © 1997 Wiley-Liss, Inc.

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    • "The significance of genetic and environmental correlation was tested by comparing the log e likelihood for two restricted models (with either r G or r E constrained to zero) against the log likelihood for the model in which these parameters were estimated. A significant genetic correlation is evidence for pleiotropy, suggesting that a gene or set of genes jointly influences both phenotypes (Almasy et al, 1997). Demographic variables including age, age 2 and sex were used as covariates in all analyses. "
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    ABSTRACT: Alcohol abuse and dependence (alcohol use disorders, AUD) are associated with brain shrinkage. Subcortical structures including amygdala, hippocampus, ventral striatum, dorsal striatum, and thalamus subserve reward functioning and may be particularly vulnerable to alcohol-related damage. These structures may also show pre-existing deficits impacting the development and maintenance of AUD. It remains unclear whether there are common genetic features underlying both subcortical volumes and AUD. In this study, structural brain images were acquired from 872 Mexican-American individuals from extended pedigrees. Subcortical volumes were obtained using FreeSurfer, and quantitative genetic analyses were performed in SOLAR. We hypothesized (1) reduced subcortical volumes in individuals with lifetime AUD relative to unrelated controls; (2) reduced subcortical volumes in individuals with current relative to past AUD (3) in non-AUD individuals, reduced subcortical volumes in those with a family history of AUD compared to those without; and (4) evidence for common genetic underpinnings (pleiotropy) between AUD risk and subcortical volumes. Results showed that individuals with lifetime AUD showed larger ventricle and smaller amygdala volumes compared to non-AUD individuals. For the amygdala, there were no differences in volume between current vs. past AUD, and non-AUD individuals with a family history of AUD demonstrated reductions compared to those with no such family history. Finally, amygdala volume was genetically correlated with risk for AUD. Together, these results suggest that reduced amygdala volume reflects a pre-existing difference rather than alcohol-induced neurotoxic damage. Our genetic correlation analysis provides evidence for a common genetic factor underlying both reduced amygdala volumes and to AUD risk.Neuropsychopharmacology accepted article preview online, 31 July 2014; doi:10.1038/npp.2014.187.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 40(2). DOI:10.1038/npp.2014.187 · 7.05 Impact Factor
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    • "To determine if any QTLs identified through linkage analysis of Max Drinks have pleiotropic effects on AUD, formal single degree of freedom LRTs were performed comparing bivariate linkage models at the location of the QTL with the estimated locus-specific heritability for AUD to ones fixed to zero [Almasy et al., 1997]. "
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    ABSTRACT: Linkage studies of alcoholism have implicated several chromosome regions, leading to the successful identification of susceptibility genes, including ADH4 and GABRA2 on chromosome 4. Quantitative endophenotypes that are potentially closer to gene action than clinical endpoints offer a means of obtaining more refined linkage signals of genes that predispose alcohol use disorders (AUD). In this study we examine a self-reported measure of the maximum number of drinks consumed in a 24-hr period (abbreviated Max Drinks), a significantly heritable phenotype (h(2) = 0.32 ± 0.05; P = 4.61 × 10(-14) ) with a strong genetic correlation with AUD (ρg = 0.99 ± 0.13) for the San Antonio Family Study (n = 1,203). Genome-wide SNPs were analyzed using variance components linkage methods in the program SOLAR, revealing a novel, genome-wide significant QTL (LOD = 4.17; P = 5.85 × 10(-6) ) for Max Drinks at chromosome 6p22.3, a region with a number of compelling candidate genes implicated in neuronal function and psychiatric illness. Joint analysis of Max Drinks and AUD status shows that the QTL has a significant non-zero effect on diagnosis (P = 4.04 × 10(-3) ), accounting for 8.6% of the total variation. Significant SNP associations for Max Drinks were also identified at the linkage region, including one, rs7761213 (P = 2.14 × 10(-4) ), obtained for an independent sample of Chinese families. Thus, our study identifies a potential risk locus for AUD at 6p22.3, with significant pleiotropic effects on the heaviness of alcohol consumption that may not be population specific. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2014; 165(4). DOI:10.1002/ajmg.b.32231 · 3.42 Impact Factor
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    • "Secondly, extended pedigrees enable the computation of genetic correlations (Almasy et al., 1997), which are a powerful way to quantify the extent to which two traits are influenced by the same additive genetic variation (also see the Transcript processing and analysis section above). In contrast to genome-wide association studies, this method is most sensitive to rare genetic variants within pedigrees, rather than to common variation across unrelated individuals. "
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    ABSTRACT: Identifying genes that contribute to white matter microstructure should provide insights into the neurobiological processes that regulate white matter development, plasticity and pathology. We detected five significant SNPs using genome-wide association analysis on a global measure of fractional anisotropy in 776 individuals from large extended pedigrees. Genetic correlations and genome-wide association results indicated that the genetic signal was largely homogeneous across white matter regions. Using RNA transcripts derived from lymphocytes in the same individuals, we identified two genes (GNA13 and CCDC91) that are likely to be cis-regulated by top SNPs, and whose expression levels were also genetically correlated with fractional anisotropy. A transcript of HTR7 was phenotypically associated with FA, and was associated with an intronic genome-wide significant SNP. These results encourage further research in the mechanisms by which GNA13, HTR7 and CCDC91 influence brain structure, and emphasize a role for g-protein signaling in the development and maintenance of white matter microstructure in health and disease.
    NeuroImage 04/2014; 97. DOI:10.1016/j.neuroimage.2014.04.021 · 6.36 Impact Factor
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