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1.  Behavioral Disinhibition and Sexual Risk Behavior among Adolescents and Young Adults in Malawi 
PLoS ONE  2013;8(9):e73574.
While behavioral factors such as early age of sexual debut, inconsistent use of condoms and multiple sexual partners have been studied in Africa, less is known about how characteristics such as impulsivity and externalizing behaviors relate to HIV-related sexual risk-taking in that region. The purpose of this study was to develop a culturally adapted behavioral disinhibition index in a sample of adolescents and young adults in Malawi. We then sought to examine the relationship between the index and sexual risk behavior as measured by multiple sexual partners and number of lifetime sexual partners.
Cross-sectional data were collected from 2342 participants in rural Malawi aged 15 to 29 years. We constructed a disinhibitory behavior score (DBS) using questions assessing disinhibitory behaviors. Bivariate analyses were conducted to assess the relationships among the individual DBS component behaviors. We utilized multivariable logistic regression to determine the association of the DBS with multiple sexual partners, and negative binomial regression to model the relationship between the DBS and number of lifetime sexual partners.
Nearly all the DBS component behaviors were significantly associated in the bivariate analyses. The DBS was associated with having multiple sexual partners (OR 1.97; 95% CI 1.57–2.48) in the multivariable logistic regression analysis. Further, negative binomial regression results demonstrated that the DBS was associated with an increased number of lifetime sexual partners (OR 1.11; 95% CI 1.07–1.16).
HIV preventive programs in Africa should take into consideration disinhibitory behaviors that may be associated with sexual risk-taking. The DBS can be used as a simple tool to identify those who may be more likely to engage in these behaviors and provide useful information regarding which groups of individuals particularly need to be targeted for behavior change interventions.
PMCID: PMC3767775  PMID: 24039987
2.  Frequency of Alcohol Use in Adolescence as a Marker for Subsequent Sexual Risk Behavior in Adulthood 
Although a number of studies have demonstrated an association between alcohol use frequency and sexual risk behavior, few have used longitudinal data. This study examined alohol use frequency in adolescence as a predictor of HIV sexual risk behavior in adulthood.
We collected data among 1368 participants in Colorado. During adolescence (Time 1), respondents were asked about the frequency of using alcohol during the previous 12 months. In adulthood (Time 2), the same respondents were asked about their sexual risk behavior during the previous 12 months. Sexual risk behavior items were used to construct an index, which was categorized to indicate low, medium and high risk study participants. The relationship between alcohol use patterns and risky sexual behavior was modeled using ordinal regression.
Compared to individuals who drank no alcohol in the past 12 months at Time 1, the odds of being in a higher risk group of sexual behavior as opposed to a lower one at Time 2 were 1.56 (95% CI, 1.04-2.35) among those who drank 6-19 times. Similarly, the odds of being in a higher risk group relative to a lower one among those who drank ≥20 times or were 1.78 (95% CI, 1.05-3.02).
Alcohol use patterns in adolescence may be useful markers for programs that aim to prevent risky sexual behavior. Based on alcohol intake patterns, it may be possible to identify frequent alcohol users that need to be targeted with appropriate alcohol use and HIV risk reduction messages.
PMCID: PMC3725214  PMID: 23587785
Alcohol; Frequency; Adolescence; Sexual risk behavior; Longitudinal
3.  Polygenic Risk Predicts Obesity in Both White and Black Young Adults 
PLoS ONE  2014;9(7):e101596.
To test transethnic replication of a genetic risk score for obesity in white and black young adults using a national sample with longitudinal data.
Design and Methods
A prospective longitudinal study using the National Longitudinal Study of Adolescent Health Sibling Pairs (n = 1,303). Obesity phenotypes were measured from anthropometric assessments when study members were aged 18–26 and again when they were 24–32. Genetic risk scores were computed based on published genome-wide association study discoveries for obesity. Analyses tested genetic associations with body-mass index (BMI), waist-height ratio, obesity, and change in BMI over time.
White and black young adults with higher genetic risk scores had higher BMI and waist-height ratio and were more likely to be obese compared to lower genetic risk age-peers. Sibling analyses revealed that the genetic risk score was predictive of BMI net of risk factors shared by siblings. In white young adults only, higher genetic risk predicted increased risk of becoming obese during the study period. In black young adults, genetic risk scores constructed using loci identified in European and African American samples had similar predictive power.
Cumulative information across the human genome can be used to characterize individual level risk for obesity. Measured genetic risk accounts for only a small amount of total variation in BMI among white and black young adults. Future research is needed to identify modifiable environmental exposures that amplify or mitigate genetic risk for elevated BMI.
PMCID: PMC4081643  PMID: 24992585
4.  Linkage Disequilibrium Mapping of the Chromosome 6q21–22.31 Bipolar I Disorder Susceptibility Locus 
We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case–control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P=6.72× 10−5) was observed in the case–control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.
PMCID: PMC4067321  PMID: 19308960
bipolar disorder; genetic; association; SLC22A16; 6q
5.  Nominal Association with CHRNA4 Variants and Nicotine Dependence 
Genes, brain, and behavior  2013;12(3):10.1111/gbb.12021.
Nicotine binds to nicotinic acetylcholine receptors and studies in animal models have shown that α4β2 receptors mediate many behavioral effects of nicotine. Human genetics studies have provided support that variation in the gene that codes for the α4 subunit influences nicotine dependence (ND), but the evidence for the involvement of the β2 subunit gene is less convincing. In the current study we examined the genetic association between variation in the genes that code for the α4 (CHRNA4) and β2 (CHRNB2) subunits of the nicotinic acetylcholine receptor and a quantitative measure of lifetime DSM-IV ND symptom counts. We performed this analysis in two longitudinal family-based studies focused on adolescent antisocial drug abuse the Center on Antisocial Drug Dependence (CADD; N = 313 families) and Genetics of Antisocial Drug Dependence (GADD; N = 111 families). Family based association tests were used to examine associations between 14 SNPs in CHRNA4 and CHRNB2 SNPs and ND symptoms. Symptom counts were corrected for age, sex and clinical status prior to the association analysis. Results when the samples were combined provided modest evidence that SNPs in CHRNA4 are associated with ND. The minor allele at both rs1044394 (A; Z=1.988, p=0.047 unadjusted p-value) and rs1044396 (G; Z=2.398, p=0.017 unadjusted p-value) was associated with increased risk of ND symptoms. These data provide suggestive evidence that variation in the α4 subunit of the nicotinic acetylcholine receptor may influence ND liability.
PMCID: PMC3727281  PMID: 23350800
Nicotine; Nicotinic Acetylcholine Receptors; DSM-IV Nicotine Dependence; Association Study
6.  Whole-Genome Pathway Analysis on 132,497 Individuals Identifies Novel Gene-Sets Associated with Body Mass Index 
PLoS ONE  2014;9(1):e78546.
Whole genome pathway analysis is a powerful tool for the exploration of the combined effects of gene-sets within biological pathways. This study applied Interval Based Enrichment Analysis (INRICH) to perform whole-genome pathway analysis of body-mass index (BMI). We used a discovery set composed of summary statistics from a meta-analysis of 123,865 subjects performed by the GIANT Consortium, and an independent sample of 8,632 subjects to assess replication of significant pathways. We examined SNPs within nominally significant pathways using linear mixed models to estimate their contribution to overall BMI heritability. Six pathways replicated as having significant enrichment for association after correcting for multiple testing, including the previously unknown relationships between BMI and the Reactome regulation of ornithine decarboxylase pathway, the KEGG lysosome pathway, and the Reactome stabilization of P53 pathway. Two non-overlapping sets of genes emerged from the six significant pathways. The clustering of shared genes based on previously identified protein-protein interactions listed in PubMed and OMIM supported the relatively independent biological effects of these two gene-sets. We estimate that the SNPs located in examined pathways explain ∼20% of the heritability for BMI that is tagged by common SNPs (3.35% of the 16.93% total).
PMCID: PMC3908858  PMID: 24497910
7.  Dietary sodium restriction reverses vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure 
We determined the efficacy of dietary sodium restriction (DSR) for improving vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure (SBP; 130–159 mmHg) and the associated physiological mechanisms.
Vascular endothelial dysfunction develops with advancing age and elevated SBP, contributing to increased cardiovascular risk. DSR lowers BP, but its effect on vascular endothelial function and mechanisms involved are unknown.
Seventeen subjects (11M/6F; 62±7 yrs, mean±S.D.) completed a randomized, crossover study of 4 weeks of both low and normal sodium intake. Vascular endothelial function (endothelium-dependent dilation; EDD), nitric oxide (NO)/tetrahydrobiopterin (BH4) bioavailability and oxidative stress-associated mechanisms were assessed following each condition.
Urinary sodium excretion was reduced by ~50% (to 70±30 mmol/day), and conduit (brachial artery flow-mediated dilation [FMDBA]) and resistance (forearm blood flow responses to acetylcholine [FBFACh]) artery EDD were 68% and 42% (peak FBFACh) higher following the low sodium diet (p<0.005). Low sodium markedly enhanced NO- mediated EDD (greater ΔFBFACh with endothelial NO synthase [eNOS] inhibition) without changing eNOS expression/activation (Ser1177 phosphorylation), restored BH4 bioactivity (less ΔFMDBA with acute BH4), abolished tonic superoxide suppression of EDD (less ΔFMDBA and ΔFBFACh with ascorbic acid infusion), and increased circulating superoxide dismutase activity (p<0.05). These effects were independent of ΔSBP. Other subject characteristics/dietary factors and endothelium-independent dilation were unchanged.
DSR largely reverses both macro- and microvascular endothelial dysfunction by enhancing NO and BH4 bioavailability and reducing oxidative stress. Our findings support the emerging concept that DSR induces “vascular protection” beyond that attributable to its BP-lowering effects.
PMCID: PMC3549053  PMID: 23141486
aging; nitric oxide; hypertension; diet; oxidative stress
8.  A Family Based Association Study of DRD4, DAT1, and 5HTT and Continuous Traits of Attention-Deficit Hyperactivity Disorder 
Behavior genetics  2011;41(1):165-174.
Despite its high heritability, genetic association studies of attention deficit-hyperactivity disorder (ADHD) have often resulted in somewhat small, inconsistent effects. Refining the ADHD phenotype beyond a dichotomous diagnosis and testing associations with continuous information from the underlying symptom dimensions may result in more consistent genetic findings. This study further examined the association between ADHD and the DRD4, DAT1, and 5HTT genes by testing their association with multivariate phenotypes derived from continuous measures of ADHD symptom severity. DNA was collected in 202 families consisting of at least one ADHD proband and at least one parent or sibling. VNTR polymorphisms of the DRD4 and DAT1 genes were significantly associated with the continuous ADHD phenotype. The association with DRD4 was driven by both inattentive and hyperactive symptoms, while the association with DAT1 was driven primarily by inattentive symptoms. These results use novel methods to build upon important connections between dopamine genes and their final behavioral manifestation as symptoms of ADHD.
PMCID: PMC3674022  PMID: 21207241
ADHD; dopamine; FBAT; genetic; serotonin
9.  Examining Associations between Disordered Eating and Serotonin Transporter Gene Polymorphisms 
The serotonin system has been implicated in mood and appetite regulation, and the serotonin transporter gene (SLC6A4) is a commonly studied candidate gene for eating pathology. However, most studies have focused on a single polymorphism (5-HTTLPR) in SLC6A4; little research has utilized multiple single nucleotide polymorphisms (SNPs) to investigate associations between SLC6A4 and eating pathology more comprehensively.
Family-based association tests were conducted for seven polymorphisms in or near SLC6A4, using families from the Colorado Center for Antisocial Drug Dependence. Data were available for 135 families, with phenotypic data available for female twins and female nontwin siblings. Seven items assessed two disordered eating characteristics: weight and shape concerns and behaviors (WSCB) and binge eating (BE).
No significant associations were found between any genetic variant and the two disordered eating characteristics.
This study suggests that utilizing polymorphisms in and near SLC6A4, including 5-HTTLPR, may not be useful in identifying genetic risk factors for disordered eating.
PMCID: PMC3323686  PMID: 22271047
eating disorders; disordered eating; serotonin transporter; family-based association; 5-HTTLPR; SNPs
10.  Externalizing Behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster 
Behavior genetics  2011;42(3):402-414.
There is strong evidence for shared genetic factors contributing to childhood externalizing disorders and substance abuse. Externalizing disorders often precede early substance experimentation, leading to the idea that individuals inherit a genetic vulnerability to generalized disinhibitory psychopathology. Genetic variation in the CHRNA5/CHRNA3/CHRNB4 gene cluster has been associated with early substance experimentation, nicotine dependence, and other drug behaviors. This study examines whether the CHRNA5/CHRNA3/CHRNB4 locus is correlated also with externalizing behaviors in three independent longitudinally assessed adolescent samples. We developed a common externalizing behavior phenotype from the available measures in the three samples, and tested for association with 10 SNPs in the gene cluster. Significant results were detected in two of the samples, including rs8040868, which remained significant after controlling for smoking quantity. These results expand on previous work focused mainly on drug behaviors, and support the hypothesis that variation in the CHRNA5/CHRNA3/CHRNB4 locus is associated with early externalizing behaviors.
PMCID: PMC3506120  PMID: 22042234
nicotinic receptor genes; externalizing behaviors; association study; disinhibition; drug behaviors
11.  Microarray analyses reveal novel targets of exercise-induced stress resistance in the dorsal raphe nucleus 
Serotonin (5-HT) is implicated in the development of stress-related mood disorders in humans. Physical activity reduces the risk of developing stress-related mood disorders, such as depression and anxiety. In rats, 6 weeks of wheel running protects against stress-induced behaviors thought to resemble symptoms of human anxiety and depression. The mechanisms by which exercise confers protection against stress-induced behaviors, however, remain unknown. One way by which exercise could generate stress resistance is by producing plastic changes in gene expression in the dorsal raphe nucleus (DRN). The DRN has a high concentration of 5-HT neurons and is implicated in stress-related mood disorders. The goal of the current experiment was to identify changes in the expression of genes that could be novel targets of exercise-induced stress resistance in the DRN. Adult, male F344 rats were allowed voluntary access to running wheels for 6 weeks; exposed to inescapable stress or no stress; and sacrificed immediately and 2 h after stressor termination. Laser capture micro dissection selectively sampled the DRN. mRNA expression was measured using the whole genome Affymetrix microarray. Comprehensive data analyses of gene expression included differential gene expression, log fold change (LFC) contrast analyses with False Discovery Rate correction, KEGG and Wiki Web Gestalt pathway enrichment analyses, and Weighted Gene Correlational Network Analysis (WGCNA). Our results suggest that physically active rats exposed to stress modulate expression of twice the number of genes, and display a more rapid and strongly coordinated response, than sedentary rats. Bioinformatics analyses revealed several potential targets of stress resistance including genes that are related to immune processes, tryptophan metabolism, and circadian/diurnal rhythms.
PMCID: PMC3650681  PMID: 23717271
Affymetrix gene microarray; Weighted Gene Correlational Network Analysis; bioinformatics; laser capture microdissection; stress resistance; dorsal raphe nucleus
12.  Gene-environment interactions related to body mass: School policies and social context as environmental moderators 
Journal of theoretical politics  2012;24(3):370-388.
This paper highlights the role of institutional resources and policies, whose origins lie in political processes, in shaping the genetic etiology of body mass among a national sample of adolescents. Using data from Waves I and II of the National Longitudinal Study of Adolescent Health, we decompose the variance of body mass into environmental and genetic components. We then examine the extent to which the genetic influences on body mass are different across the 134 schools in the study. Taking advantage of school differences in both health-related policies and social norms regarding body size, we examine how institutional resources and policies alter the relative impact of genetic influences on body mass. For the entire sample, we estimate a heritability of .82, with the remaining .18 due to unique environmental factors. However, we also show variation about this estimate and provide evidence suggesting that social norms and institutional policies often mask genetic vulnerabilities to increased weight. Empirically, we demonstrate that more-restrictive school policies and policies designed to curb weight gain are also associated with decreases the proportion of variance in body mass that is due to additive genetic influences.
PMCID: PMC3518081  PMID: 23236222
policies; gene-environment interactions; BMI; obesity; schools
13.  Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database 
PLoS Genetics  2012;8(3):e1002548.
More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ∼27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P<5×10−8) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3×10−8). All meta-analysis results are freely available on a dedicated online database (, which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
Author Summary
The genetic basis of Parkinson's disease is complex, i.e. it is determined by a number of different disease-causing and disease-predisposing genes. Especially the latter have proven difficult to find, evidenced by more than 800 published genetic association studies, typically showing discrepant results. To facilitate the interpretation of this large and continuously increasing body of data, we have created a freely available online database (“PDGene”: which provides an exhaustive account of all published genetic association studies in PD. One particularly useful feature is the calculation and display of up-to-date summary statistics of published data for overlapping DNA sequence variants (polymorphisms). These meta-analyses revealed eleven gene loci that showed a statistically very significant (P<5×10−8; a.k.a. genome-wide significance) association with risk for PD: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, SYT11/RAB25. In addition and purely by data-mining, we identified one novel PD susceptibility locus in a gene called ITGA8 (rs7077361, P = 1.3×10−8). We note that our continuously updated database represents the most comprehensive research synopsis of genetic association studies in PD to date. In addition to vastly facilitating the work of other PD geneticists, our approach may serve as a valuable example for other complex diseases.
PMCID: PMC3305333  PMID: 22438815
14.  Mutational load analysis of unrelated individuals 
BMC Proceedings  2011;5(Suppl 9):S55.
Evolutionary genetic models predict that the cumulative effect of rare deleterious mutations across the genome—known as mutational load burden—increases the susceptibility to complex disease. To test the mutational load burden hypothesis, we adopted a two-tiered approach: assessing the impact of whole-exome minor allele load burden and then conducting individual-gene screening. For our primary analysis, we examined various minor allele frequency (MAF) thresholds and weighting schemes to examine the overall effect of minor allele load on affection status. We found a consistent association between minor allele load and affection status, but this effect did not markedly increase within rare and/or functional single-nucleotide polymorphisms (SNPs). Our follow-up analysis considered minor allele load in individual genes to see whether only one or a few genes were driving the overall effect. Examining our most significant result—minor allele load of nonsynonymous SNPs with MAF < 2.4%—we detected no significantly associated genes after Bonferroni correction for multiple testing. After moderately significant genes (p < 0.05) were removed, the overall effect of rare nonsynonymous allele load remained significant. Overall, we did not find clear support for mutational load burden on affection status; however, these results are ultimately dependent on and limited by the nature of the Genetic Analysis Workshop 17 simulation.
PMCID: PMC3287893  PMID: 22373138
15.  Recent methods for polygenic analysis of genome-wide data implicate an important effect of common variants on cardiovascular disease risk 
BMC Medical Genetics  2011;12:146.
Traditional genome-wide association studies are generally limited in their ability explain a large portion of genetic risk for most common diseases. We sought to use both traditional GWAS methods, as well as more recently developed polygenic genome-wide analysis techniques to identify subsets of single-nucleotide polymorphisms (SNPs) that may be involved in risk of cardiovascular disease, as well as estimate the heritability explained by common SNPs.
Using data from the Framingham SNP Health Association Resource (SHARe), three complimentary methods were applied to examine the genetic factors associated with the Framingham Risk Score, a widely accepted indicator of underlying cardiovascular disease risk. The first method adopted a traditional GWAS approach - independently testing each SNP for association with the Framingham Risk Score. The second two approaches involved polygenic methods with the intention of providing estimates of aggregate genetic risk and heritability.
While no SNPs were independently associated with the Framingham Risk Score based on the results of the traditional GWAS analysis, we were able to identify cardiovascular disease-related SNPs as reported by previous studies. A predictive polygenic analysis was only able to explain approximately 1% of the genetic variance when predicting the 10-year risk of general cardiovascular disease. However, 20% to 30% of the variation in the Framingham Risk Score was explained using a recently developed method that considers the joint effect of all SNPs simultaneously.
The results of this study imply that common SNPs explain a large amount of the variation in the Framingham Risk Score and suggest that future, better-powered genome-wide association studies, possibly informed by knowledge of gene-pathways, will uncover more risk variants that will help to elucidate the genetic architecture of cardiovascular disease.
PMCID: PMC3213201  PMID: 22029572
16.  Genetic Dissection of Dietary Restriction in Mice Supports the Metabolic Efficiency Model of Life Extension 
Experimental gerontology  2010;45(9):691-701.
Dietary restriction (DR) has been used for decades to retard aging in rodents, but its mechanism of action remains an enigma. A principal roadblock has been that DR affects many different processes, making it difficult to distinguish cause and effect. To address this problem, we applied a quantitative genetics approach utilizing the ILSXISS series of mouse recombinant inbred strains. Across 42 strains, mean female lifespan ranged from 380 to 1070 days on DR (fed 60% of ad libitum [AL]) and from 490 to 1020 days on an AL diet. Longevity under DR and AL is under genetic control, showing 34% and 36% heritability, respectively. There was no correlation between lifespans on DR and AL; thus different genes modulate longevity under the two regimens. DR lifespans are significantly correlated with female fertility after return to an AL diet after various periods of DR (R = 0.44, P = 0.006). We assessed fuel efficiency (FE, ability to maintain growth and body weight independent of absolute food intake) using a multivariate approach and found it to be correlated with longevity and female fertility, suggesting possible causality. We found several quantitative trait loci responsible for these traits, mapping to chromosomes 7, 9, and 15. We present a metabolic model in which the anti-aging effects of DR are consistent with the ability to efficiently utilize dietary resources.
PMCID: PMC2926251  PMID: 20452416
aging; food restriction; lifespan; fertility; metabolic efficiency; quantitative trait loci; genetic mapping; physiology
17.  Ethnicity, Body Mass, and Genome-Wide Data 
Biodemography and social biology  2010;56(2):123-136.
This article combines social and genetic epidemiology to examine the influence of self-reported ethnicity on body mass index (BMI) among a sample of adolescents and young adults. We use genetic information from more than 5,000 single nucleotide polymorphisms in combination with principal components analysis to characterize population ancestry of individuals in this study. We show that non-Hispanic white and Mexican-American respondents differ significantly with respect to BMI and differ on the first principal component from the genetic data. This first component is positively associated with BMI and accounts for roughly 3% of the genetic variance in our sample. However, after controlling for this genetic measure, the observed ethnic differences in BMI remain large and statistically significant. This study demonstrates a parsimonious method to adjust for genetic differences among individual respondents that may contribute to observed differences in outcomes. In this case, adjusting for genetic background has no bearing on the influence of self-identified ethnicity.
PMCID: PMC3155265  PMID: 21387985
18.  An omnibus test for family-based association studies with multiple SNPs and multiple phenotypes 
We propose an omnibus family-based association test (MFBAT) that can be applied to multiple markers and multiple phenotypes and that has only one degree of freedom. The proposed test statistic extends current FBAT methodology to incorporate multiple markers as well as multiple phenotypes. Using simulation studies, power estimates for the proposed methodology are compared with the standard methodologies. On the basis of these simulations, we find that MFBAT substantially outperforms other methods, including haplotypic approaches and doing multiple tests with single single-nucleotide polymorphisms (SNPs) and single phenotypes. The practical relevance of the approach is illustrated by an application to asthma in which SNP/phenotype combinations are identified and reach overall significance that would not have been identified using other approaches. This methodology is directly applicable to cases in which there are multiple SNPs, such as candidate gene studies, cases in which there are multiple phenotypes, such as expression data, and cases in which there are multiple phenotypes and genotypes, such as genome-wide association studies that incorporate expression profiles as phenotypes. This program is available in the PBAT analysis package.
PMCID: PMC2874662  PMID: 20087406
family-based association testing (FBAT); genome-wide association studies; FBAT-PC; multiple marker; multiple phenotypes; multiple testing
19.  Association of CHRN genes with “dizziness” to tobacco 
The neuronal nicotinic receptor genes (CHRN) have been implicated in a variety of smoking-related behaviors. Here we tested for association between an early subjective response phenotype, “dizziness,” and 226 SNPs in CHRN genes. The sample included 789 nicotine-dependent cases and 811 controls, where early “dizziness” reports were significantly associated with case/control status (p<0.0001). Multiple SNPs in the putative promoter region of the CHRNB3 gene were nominally associated with “dizziness” experience from the first few cigarettes (p<0.01). Cell culture studies were conducted to examine the ability of different haplotypes in the CHRNB3 promoter to drive luciferase expression. Data from these experiments supports the hypothesis that different alleles in the CHRNB3 upstream promoter region may lead to different levels of RNA expression. In addition, a novel finding of association between SNPs in the CHRNA10 gene reached experiment-wide empirical significance (p=0.048), which implicates another CHRN gene as being involved in early subjective response to tobacco.
PMCID: PMC2878135  PMID: 19760673
nicotinic receptors; genetics; subjective effects; tobacco; gene expression; humans
20.  Test of association between GABRA2 (SNP rs279871) and adolescent conduct/alcohol use disorders utilizing a sample of clinic referred youth with serious substance and conduct problems, controls and available first degree relatives 
Drug and alcohol dependence  2009;106(2-3):199-203.
Recent findings have linked the GABRA2 gene with antisocial personality disorder and alcohol dependence (AD) in adults and conduct disorder (CD), but not AD symptoms, in children and adolescents. We sought to replicate previous findings and test for an association between a single nucleotide polymorphism (SNP) in the GABRA2 gene (rs279871) and CD among adolescents.
Adolescent patients (n=371), 13-18 years old, were recruited from a university substance abuse treatment program. Patient siblings (n=245), parents of patients (n=355), adolescent controls (n=185), siblings of controls (n=163) and parents of controls (n=263) were included in these analyses (total sample n=1,582). Case-control (using only Caucasian and Hispanic probands) and family-based association tests were completed to test for association between rs279871 and several a priori CD and AD phenotypes.
For case-control association tests, rs279871 was significantly associated with CD (p=0.02) but not AD phenotypes; the result did not survive strict correction for multiple testing. All family-based association tests were non-significant (CD p=0.48; CD symptom count age corrected within sex p=0.91; AD p=0.84; alcohol use disorder p=0.52).
Consistent with previous findings, the results do not support the association between GABRA2 SNP rs279871 and AD in adolescents. Our results also do not support an association between rs279871 and CD; the study limitations are reviewed.
PMCID: PMC2841007  PMID: 19783384
Externalizing Disorders; Disruptive Behavior; Antisocial
21.  An omnibus test for family-based association studies with multiple SNPs and multiple phenotypes 
We propose an omnibus family-based association test (MFBAT), that can be applied to multiple markers and multiple phenotypes and that has only 1 degree of freedom. The proposed test statistic extends current FBAT methodology to incorporate multiple markers as well as multiple phenotypes. Using simulation studies, power estimates for the proposed methodology are compared with the standard methodologies. Based on these simulations, we find that MFBAT substantially outperforms other methods including some haplotypic approaches and doing multiple tests with single SNPs and single phenotypes. The practical relevance of the approach is illustrated by an application to asthma where SNPs/phenotype combinations are identified and reach overall significance that would not have been identified using other approaches. This methodology is directly applicable to cases where there are multiple SNPs, such as candidate gene studies, cases where there are multiple phenotypes, such as expression data, and cases where there are multiple phenotypes and genotypes, such as genome-wide association studies that incorporate expression profiles as phenotypes. This program is available in the PBAT analysis package1.
PMCID: PMC2874662  PMID: 20087406
Family-based association testing (FBAT); genome-wide association studies; FBAT-PC; multiple marker; multiple phenotypes; multiple testing
Behavior genetics  2010;40(4):495-504.
The transition between adolescence and young adulthood is a developmentally sensitive time where children are at an increased risk for becoming overweight and developing obesity. Twin studies have reported that body mass index [BMI] is highly heritable, however, it remains unclear whether the genetic influences are sex-limited and whether non-additive genetic influences contribute to body mass index [BMI] during these ages. In the current report, we examined self-reported data on BMI in same [n= 2744] and opposite-sex [n = 1178] siblings participating in the National Longitudinal Study on Adolescent Health [Add Health]. To investigate whether the same or different genes contributed to BMI for both sexes, we fit quantitative sex-limited genetic models to three waves of data collection. At each of the three Waves of assessment, models that included additive genetic, individual-specific environment, and no sex-limited genetic influences fit the data most parsimoniously. Heritable effects on BMI at each of the three Waves were large for both sexes and ranged between 0.75 and 0.86. While genetic contributions across the ages were highly correlated, longitudinal analyses indicated that the relevant individual-specific environmental influences on BMI in adolescence and young adulthood change sizably. These results underscore the importance of understanding early genetic influences on BMI and highlight the role environmental experiences have at later ages when new genetic influences appear to make a small contribution to individual variation in BMI.
PMCID: PMC2989725  PMID: 20087641
23.  Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample 
Neuronal nicotinic acetylcholine receptors are activated by both endogenous acetylcholine and exogenous nicotine, making sequence variations in these receptors likely candidates for association with tobacco phenotypes. Previous studies have found evidence for significant association between SNPs in the genomic region containing the CHRNA6 and CHRNB3 genes and tobacco behaviors (Bierut et al, 2007; Greenbaum et al, 2006; Saccone et al, 2007; Zeiger et al, 2008). In this study, we provide support for an association between these genes and tobacco dependence in the National Youth Survey Family Study wave 10, a nationally representative sample of households. Eight single nucleotide polymorphisms (SNPs) in the CHRNA6 and CHRNB3 genomic region were genotyped in 1051 subjects, approximately half of whom are members of sibling pairs. Genetic association with DSM-IV dependence was assessed using a family-based approach as implemented in the statistical package PBAT. Individual SNPs were tested for association with quit attempts and overall dependence. Variation in CHRNA6 was found to be associated with tobacco dependence (p=0.007 in Caucasians). SNPs in CHRNB3 were found to be associated with the number of quit attempts (p=0.0024). Together these results further implicate the region downstream of CHRNA6 and the region upstream of CHRNB3 in risk of nicotine dependence.
PMCID: PMC2915837  PMID: 18704094
Nicotinic receptors; SNP; Genetic association; Tobacco use; Nicotine Dependence
24.  SNPs in CHRNA6 and CHRNB3 are associated with alcohol consumption in a nationally representative sample 
Genes, brain, and behavior  2009;8(6):631-637.
The CHRNA6 and CHRNB3 genes have been associated with nicotine dependence and early subjective response to nicotine (Bierut et al., 2007; Hoft et al., 2008; Saccone et al., 2007; Zeiger et al., 2008). Here we present evidence, using a nationally representative sample of adults, that this region is also associated with alcohol behaviors. Six SNPs spanning the CHRNB3/A6 genes were analyzed using the statistical genetics software FBAT-PC (Lange et al., 2004b), which allows one to examine a collection of multiple phenotypes to generate a maximally heritable composite phenotype for each SNP. The six SNPs were tested using FBAT-PC including four alcohol phenotypes: average number of drinks, blackouts, total number of DSM-IV abuse and dependence symptoms endorsed, and quit attempts. Three SNPs in CHRNA6 (rs1072003 p=0.015, rs892413 p=0.0033, and rs2304297 p=0.012) and one SNPs in CHRNB3 (rs13280604 p = 0.0053) were associated with a composite of the alcohol phenotypes. The association was primarily driven by the average number of drinks.
PMCID: PMC2880622  PMID: 19500157
Nicotinic receptors; SNP; Genetic association; Alcohol use; Alcohol Dependence
25.  Assessment of Alzheimer’s disease case–control associations using family-based methods  
Neurogenetics  2008;10(1):19-25.
The genetics of Alzheimer’s disease (AD) is heterogeneous and remains only ill-defined. We have recently created a freely available and continuously updated online database (AlzGene; for which we collect all published genetic association studies in AD and perform systematic meta-analyses on all polymorphisms with sufficient genotype data. In this study, we tested 27 genes (ACE, BDNF, CH25H, CHRNB2, CST3, CTSD, DAPK1, GALP, hCG2039140, IL1B, LMNA, LOC439999, LOC651924, MAPT, MTHFR, MYH13, PCK1, PGBD1, PRNP, PSEN1, SORCS1, SORL1, TF, TFAM, TNK1, GWA_14q32.13, and GWA_7p15.2), all showing significant association with AD risk in the AlzGene meta-analyses, in a large collection of family-based samples comprised of 4,180 subjects from over 1,300 pedigrees. Overall, we observe significant association with risk for AD and polymorphisms in ACE, CHRNB2, TF, and an as yet uncharacterized locus on chromosome 7p15.2 [rs1859849]. For all four loci, the association was observed with the same alleles as in the AlzGene meta-analyses. The convergence of case–control and family-based findings suggests that these loci currently represent the most promising AD gene candidates. Further fine-mapping and functional analyses are warranted to elucidate the potential biochemical mechanisms and epidemiological relevance of these genes.
PMCID: PMC2841132  PMID: 18830724
Alzheimer’s disease; Risk factors; Genetic association; Meta-analysis; Family-based association testing

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