Genomic screen for substance dependence and body mass index in Southwest California Indians

ArticleinGenes Brain and Behavior 6(2):184-91 · April 2007with4 Reads
DOI: 10.1111/j.1601-183X.2006.00246.x · Source: PubMed
Abstract
Substance abuse and obesity are health disparities that may afflict Native Americans more than some other ethnic groups. One theoretical assumption concerning Native people is that the long history of dependence on foraging and subsistence agriculture may have led to selective enrichment of traits that improve genetic fitness, so called 'thrifty' or 'fat sparing' genes. We have speculated that this same selective pressure may have enriched for genetic variants that increase the risk for consumption of alcohol and drugs of abuse. Here, we report the results of a genome scan that compared findings for two consumption phenotypes: 'any drug dependence and/or regular tobacco use' and body mass index (BMI) in southwest California (SWC) Indian families. Variance component analyses from SOLAR were used to generate log of the odds ratio (LOD) scores. Evidence for linkage was found on chromosome 6 for both the 'any drug' (LOD score = 3.3) and BMI (LOD score = 2.3) phenotypes. Bivariate analyses of the two phenotypes revealed a combined LOD score of 4.1 at that location. Additional loci on chromosomes 6, 15, 16 and 21 were found for the 'any drug' phenotype, and on chromosomes 8, 16 and 18 for BMI (LOD scores ranged between 1.2 and 2.3). These results provide suggestive evidence for linkage for substance abuse and BMI in this Mission Indian population and, furthermore, provide preliminary data suggesting that 'consumption phenotypes' may share some genetic determinants.
    • "If the cost of WGS falls, the current relative economic advantage of fixed content genotyping arrays is expected to decline in favor of the more comprehensive WGS. The current report is part of an ongoing family study to identify sequence variants that predispose to substance dependence in a community sample of American Indians1011121314. The specific aims of this report were to (1) validate the low-coverage WGS approach by comparing different variant calling approaches and the resulting variant calls from low-coverage WGS (3-12X seeFigure 1 ) to genotypes for approximately 200,000 polymorphic variants measured with a first generation Axiom Affymetrix Exome Chip array and (2) provide a preliminary demonstration of the utility of the called variant data obtained from low-coverage WGS by investigating the kinship structure and calculating founder allele frequencies for this sample. "
    [Show abstract] [Hide abstract] ABSTRACT: The reduction in the cost of sequencing a human genome has led to the use of genotype sampling strategies in order to impute and infer the presence of sequence variants that can then be tested for associations with traits of interest. Low-coverage Whole Genome Sequencing (WGS) is a sampling strategy that overcomes some of the deficiencies seen in fixed content SNP array studies. Linkage-disequilibrium (LD) aware variant callers, such as the program Thunder, may provide a calling rate and accuracy that makes a low-coverage sequencing strategy viable. We examined the performance of an LD-aware variant calling strategy in a population of 708 low-coverage whole genome sequences from a community sample of Native Americans. We assessed variant calling through a comparison of the sequencing results to genotypes measured in 641 of the same subjects using a fixed content first generation exome array. The comparison was made using the variant calling routines GATK Unified Genotyper program and the LD-aware variant caller Thunder. Thunder was found to improve concordance in a coverage dependent fashion, while correctly calling nearly all of the common variants as well as a high percentage of the rare variants present in the sample. Low-coverage WGS is a strategy that appears to collect genetic information intermediate in scope between fixed content genotyping arrays and deep-coverage WGS. Our data suggests that low-coverage WGS is a viable strategy with a greater chance of discovering novel variants and associations than fixed content arrays for large sample association analyses.
    Full-text · Article · Jan 2014
    • "American Indians and Mexican Americans have an increase in some risk factors for cardiovascular disease such as alcohol and tobacco use [9]. We have previously reported the presence of several cardiovascular risk factors including alcohol abuse and dependence in this sample of American Indians and Mexican Americans (e.g., [4,26272829). However, our current results show that the incidence of alcohol and tobacco use and dependence is not different between obese and nonobese participants. "
    [Show abstract] [Hide abstract] ABSTRACT: Obesity is a serious public health problem, especially in some minority communities, and it has been associated with an increased risk of cardiovascular diseases. While obesity is a serious health concern in both American Indian and Mexican American populations, the relationship between obesity and cardiac autonomic control in these two populations is not well understood. The present study in a selected sample of American Indians and Mexican Americans assessed associations between obesity, blood pressure (BP), and cardiovascular autonomic control. Cardiovascular autonomic control, systolic and diastolic mean BP, and body mass index were obtained from one hundred thirty-two American Indian and Mexican American men and women who are literate in English and are residing legally in San Diego County. Men had a significant greater systolic and diastolic BP and were more likely to develop systolic prehypertension and hypertension than women. Obese participants showed greater mean heart rate (HR) and systolic and diastolic BP than nonobese participants. Obese men also exhibited greater cardiac sympathetic activity and lower cardiovagal control than obese women. These results suggest that obesity and gender differences in cardiovascular autonomic control may contribute to risk for cardiovascular disorders in this sample of American Indians and Mexican Americans.
    Full-text · Article · Aug 2013
    • "One location that provided suggestive evidence of linkage was on chromosome 12p13.33-13.32 at 5 cM that had a LOD score of 2.11. A number of previous studies in this Indian population have found evidence or suggested evidence for linkage for a number of phenotypes associated with substance dependence including alcohol dependence phenotypes (Ehlers et al., 2004b), alcohol craving (Ehlers and Wilhelmsen, 2005), tobacco usage (), cannabis dependence phenotypes (Ehlers et al., 2009), externalizing diagnoses (Ehlers et al., 2008a), Body Mass Index (Ehlers and Wilhelmsen, 2007), EEG phenotypes (Ehlers et al., 2010c), and level of response to alcohol (Ehlers et al., 2010d). None of these studies found evidence or suggestive evidence for linkage at the site on chromosome 12 identified for the STIM craving phenotype in the present study suggesting that it may be unique to this phenotype in this population. "
    [Show abstract] [Hide abstract] ABSTRACT: Amphetamine-type substances are the second most widely used illicit drugs in the United States. There is evidence to suggest that stimulant use (cocaine and methamphetamine) has a heritable component, yet the areas of the genome underlying these use disorders are yet to be identified. This study's aims were to map loci linked to stimulant dependence, heavy use, and craving in an American Indian community at high risk for substance dependence. DSM diagnosis of stimulant dependence, as well as indices of stimulant "craving," and "heavy use," were obtained using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms in 381 members of multiplex families using SOLAR. Stimulant dependence, stimulant "craving," and "heavy stimulant use," were all found to be heritable. Analyses of multipoint variance component LOD scores, failed to yield evidence of linkage for stimulant dependence. For the stimulant "craving" phenotype, linkage analysis revealed a locus that had a LOD score of 3.02 on chromosome 15q25.3-26.1 near the nicotinic receptor gene cluster. A LOD score of 2.05 was found at this same site for "heavy stimulant use." Additional loci with LOD scores above 2.00 were found for stimulant "craving" on chromosomes 12p13.33-13.32 and 18q22.3. These results corroborate the importance of "craving" as an important phenotype that is associated with regions on chromosome 12, 15, and 18, that have been highlighted in prior segregation studies in this and other populations for substance dependence-related phenotypes.
    Article · Dec 2011
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