A generalized weighted quantile sum approach for analyzing correlated data in the presence of interactions.

A weighted quantile sum (WQS) regression has been used to assess the associations between environmental exposures and health outcomes. However, the currently available WQS approach, which is based on additive effects, does not allow exploring for potential interactions of exposures with other covariates in relation to a health outcome. In addition, the current WQS cannot account for clustering, thus it may not be valid for analysis of clustered data. We propose a generalized WQS approach that can assess interactions by estimating stratum-specific weights of exposures in a mixture, while accounting for potential clustering effect of matched pairs of cases and controls as well as censored exposure data due to being below the limits of detection. The performance of the proposed method in identifying interactions is evaluated through simulations based on various scenarios of correlation structures among the exposures and with an outcome. We also assess how well the proposed method performs in the presence of the varying levels of censoring in exposures. Our findings from the simulation study show that the proposed method outperforms the traditional WQS, as indicated by higher power of detecting interactions. We also find no strong evidence that the proposed method falsely identifies interactions when there are no true interactive effects. We demonstrate application of the proposed method to real data from the Epidemiological Research on Autism Spectrum Disorder (ASD) in Jamaica (ERAJ) by examining interactions between exposure to manganese and glutathione S-transferase family gene, GSTP1 in relation to ASD.

Maternal Exposures Associated with Autism Spectrum Disorder in Jamaican Children.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with poorly understood etiology. Many maternal exposures during pregnancy and breastfeeding potentially interfere with neurodevelopment. Using data from two age- and sex-matched case-control studies in Jamaica (n = 298 pairs), results of conditional logistic regression analyses suggest that maternal exposures to fever or infection (matched odds ratio (MOR) = 3.12, 95% CI 1.74-5.60), physical trauma (MOR 2.02, 95% CI 1.01-4.05), and oil-based paints (MOR 1.99, 95% CI 1.14-3.46) may be associated with ASD. Additionally, maternal exposure to oil-based paints may modify the relationship between maternal exposure to pesticides and ASD, which deepens our understanding of the association between pesticides and ASD.

The diagnosis of autism and autism spectrum disorder in low- and middle-income countries: Experience from Jamaica.

The administration requirements of the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised, widely used in high-income countries, make them less feasible for diagnosis of autism spectrum disorder in low- and middle-income countries. The flexible administration requirements of the Childhood Autism Rating Scale have resulted in its use in both high-income countries and low- and middle-income countries. This study examines the agreement between assessments using the Childhood Autism Rating Scale with those using the Autism Diagnostic Observation Schedule or Autism Diagnostic Observation Schedule, Second Edition and Autism Diagnostic Interview-Revised in Jamaica. Children aged 2-8 years (n = 149) diagnosed with autism by an experienced clinician using the Childhood Autism Rating Scale were re-evaluated using the Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised. The proportion diagnosed with autism spectrum disorder using the Autism Diagnostic Observation Schedule, Autism Diagnostic Observation Schedule, Second Edition, and Autism Diagnostic Interview-Revised was determined and mean domain scores compared using analysis of variance (ANOVA). The mean age was 64.4 (standard deviation = 21.6) months; the male:female ratio was 6:1. The diagnostic agreement of the Childhood Autism Rating Scale with the Autism Diagnostic Observation Schedule and Autism Diagnostic Observation Schedule, Second Edition was 100.0% and 98.0%, respectively. Agreement with the Autism Diagnostic Interview-Revised was 94.6%. Domain scores were highest for children with more severe symptoms (p < 0.01). Despite a high level of agreement of the Childhood Autism Rating Scale with the Autism Diagnostic Observation Schedule, Autism Diagnostic Observation Schedule, Second Edition, and Autism Diagnostic Interview-Revised, the Childhood Autism Rating Scale should be evaluated further with a broader range of autism spectrum disorder symptomatology, and by clinicians with varying experience before recommendation for use in low- and middle-income countries.

Role of Metabolic Genes in Blood Aluminum Concentrations of Jamaican Children with and without Autism Spectrum Disorder.

Aluminum is a neurotoxic metal with known health effects in animals and humans. Glutathione-S-transferase (GST) genes and enzymes play a major role in detoxification of several heavy metals. Besides a direct relationship with oxidative stress; aluminum decreases GST enzyme activities. Using data from 116 Jamaican children; age 2-8 years; with Autism Spectrum Disorder (ASD) and 116 sex- and age-matched typically developing (TD) children; we investigated the association of polymorphisms in three GST genes (GSTP1; GSTM1; and GSTT1) with mean blood aluminum concentrations in children with and without ASD. Using log-transformed blood aluminum concentration as the dependent variable in a linear regression model; we assessed the additive and interactive effects of ASD status and polymorphisms in the three aforementioned GST genes in relation to blood aluminum concentrations. Although none of the additive effects were statistically significant (all p > 0.16); we observed a marginally significant interaction between GSTP1 Ile105Val (rs1695) and ASD status (p = 0.07); even after controlling for parental education level and consumption of avocado; root vegetables; and tuna (canned fish). Our findings indicate a significantly lower (p < 0.03) adjusted geometric mean blood aluminum concentration for TD children who had the Val/Val genotype (14.57 µg/L); compared with those with Ile/Ile or Ile/Val genotypes who had an adjusted geometric mean of 23.75 µg/L. However; this difference was not statistically significant among the ASD cases (p = 0.76). Our findings indicate that ASD status may be a potential effect modifier when assessing the association between GSTP1 rs1695 and blood aluminum concentrations among Jamaican children. These findings require replication in other populations.

Concentrations of Polychlorinated Biphenyls and Organochlorine Pesticides in Umbilical Cord Blood Serum of Newborns in Kingston, Jamaica.

To date much of the biomonitoring related to exposure to polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides is from middle to high income countries, including the U.S., Canada and Europe, but such data are lacking for the majority of low to middle income countries. Using data from 64 pregnant mothers who were enrolled in 2011, we aimed to assess the concentrations of the aforementioned toxins in umbilical cord blood serum of 67 Jamaican newborns. For 97 of the 100 PCB congeners and 16 of the 17 OC pesticides, all (100%) concentrations were below their respective limits of detection (LOD). Mean (standard deviation (SD)) lipid-adjusted concentrations in cord blood serum for congeners PCB-153, PCB-180, PCB-206 and total PCB were 14.25 (3.21), 7.16 (1.71), 7.30 (1.74) and 28.15 (6.03) ng/g-lipid, respectively. The means (SD) for the 4,4'-dichlorodiphenyldichloroethylene (DDE)-hexane fraction and total-DDE were 61.61 (70.78) and 61.60 (70.76) ng/g-lipid, respectively. Compared to the U.S. and Canada, the concentrations of these toxins were lower in cord-blood serum of Jamaican newborns. We discuss that these differences could be partly due to differences in dietary patterns in these countries. Despite limitations in our dataset, our results provide information on the investigated toxins in cord blood serum that could serve as a reference for Jamaican newborns.

Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease.

INTRODUCTION: We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. METHODS: We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. RESULTS: We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). DISCUSSION: Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.

Factors associated with blood lead concentrations of children in Jamaica.

Lead is a heavy metal known to be detrimental to neurologic, physiologic, and behavioral health of children. Previous studies from Jamaica reported that mean lead levels in soil are four times that of lead levels in some other parts of the world. Other studies detected lead levels in fruits and root vegetables, which were grown in areas with lead contaminated soil. In this study, we investigate environmental factors associated with blood lead concentrations in Jamaican children. The participants in this study comprised 125 typically developing (TD) children (ages 2-8 years) who served as controls in an age- and sex-matched case-control study that enrolled children from 2009-2012 in Jamaica. We administered a questionnaire to assess demographic and socioeconomic information as well as potential exposures to lead through food. Using General Linear Models (GLMs), we identified factors associated with blood lead concentrations in Jamaican children. The geometric mean blood lead concentration (GMBLC) in the sample of children in this study was 2.80 µg dL(-1). In univariable GLM analyses, GMBLC was higher for children whose parents did not have education beyond high school compared to those whose parents had attained this level (3.00 µg dL(-1) vs. 2.31 µg dL(-1); P = 0.05), children living near a high traffic road compared to those who did not (3.43 µg dL(-1) vs. 2.52 µg dL(-1); P < 0.01), and children who reported eating ackee compared to those who did not eat this fruit (2.89 µg dL(-1) vs. 1.65 µg dL(-1); P < 0.05). In multivariable analysis, living near a high traffic road was identified as an independent risk factor for higher adjusted GMBLC (3.05 µg dL(-1) vs. 2.19 µg dL(-1); P = 0.01). While our findings indicate that GMBLC in Jamaican children has dropped by at least 62% during the past two decades, children living in Jamaica still have GMBLC that is twice that of children in more developed countries. In addition, we have identified significant risk factors for higher blood lead concentrations in Jamaican children. We believe increasing awareness among parents regarding these risk factors could potentially lead to a lower level of lead exposure in Jamaican children.

Concentration of lead, mercury, cadmium, aluminum, arsenic and manganese in umbilical cord blood of Jamaican newborns.

The objective of this study was to characterize the concentrations of lead, mercury, cadmium, aluminum, and manganese in umbilical cord blood of Jamaican newborns and to explore the possible association between concentrations of these elements and certain birth outcomes. Based on data from 100 pregnant mothers and their 100 newborns who were enrolled from Jamaica in 2011, the arithmetic mean (standard deviation) concentrations of cord blood lead, mercury, aluminum, and manganese were 0.8 (1.3 µg/dL), 4.4 (2.4 µg/L), 10.9 (9.2 µg/L), and 43.7 (17.7 µg/L), respectively. In univariable General Linear Models, the geometric mean cord blood aluminum concentration was higher for children whose mothers had completed their education up to high school compared to those whose mothers had any education beyond high school (12.2 µg/L vs. 6.4 µg/L; p < 0.01). After controlling for maternal education level and socio-economic status (through ownership of a family car), the cord blood lead concentration was significantly associated with head circumference (adjusted p < 0.01). Our results not only provide levels of arsenic and the aforementioned metals in cord blood that could serve as a reference for the Jamaican population, but also replicate previously reported significant associations between cord blood lead concentrations and head circumference at birth in other populations.

Blood lead concentrations in Jamaican children with and without autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder manifesting by early childhood. Lead is a toxic metal shown to cause neurodevelopmental disorders in children. Several studies have investigated the possible association between exposure to lead and ASD, but their findings are conflicting. Using data from 100 ASD cases (2-8 years of age) and their age- and sex-matched typically developing controls, we investigated the association between blood lead concentrations (BLC) and ASD in Jamaican children. We administered a questionnaire to assess demographic and socioeconomic information as well as exposure to potential lead sources. We used General Linear Models (GLM) to assess the association of BLC with ASD status as well as with sources of exposure to lead. In univariable GLM, we found a significant difference between geometric mean blood lead concentrations of ASD cases and controls (2.25 µg/dL cases vs. 2.73 µg/dL controls, p < 0.05). However, after controlling for potential confounders, there were no significant differences between adjusted geometric mean blood lead concentrations of ASD cases and controls (2.55 µg/dL vs. 2.72 µg/dL, p = 0.64). Our results do not support an association between BLC and ASD in Jamaican children. We have identified significant confounders when assessing an association between ASD and BLC.

Blood manganese concentrations in Jamaican children with and without autism spectrum disorders.

BACKGROUND: Manganese is an essential element for human health and development. Previous studies have shown neurotoxic effects in children exposed to higher levels of manganese. Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that impairs social interaction and communication. Several studies have hypothesized that ASD is caused through environmental exposures during crucial stages in brain development. We investigated the possible association between blood manganese concentrations (BMC) and ASD. We also identified factors associated with BMC in typically developing (TD) Jamaican children. METHODS: We used data from 109 ASD cases with their 1:1 age- and sex-matched TD controls to compare mean BMC in Jamaican children (2-8 years of age) with and without ASD. We administered a pre-tested questionnaire to assess demographic and socioeconomic information, medical history, and potential exposure to manganese. Finally, we collected 2 mL of whole blood from each child for analysis of manganese levels. Using General Linear Models (GLM), we assessed the association between BMC and ASD status. Furthermore, we used two independent sample t-tests to identify factors associated with BMC in TD children. RESULTS: In univariable GLM analysis, we found no significant association between BMC and ASD, (10.9 µg/L for cases vs. 10.5 µg/L for controls; P = 0.29). In a multivariable GLM adjusting for paternal age, parental education, place of child's birth (Kingston parish), consumption of root vegetables, cabbage, saltwater fish, and cakes/buns, there was still no significant association between BMC and ASD status, (11.5 µg/L for cases vs. 11.9 µg/L for controls; P = 0.48). Our findings also indicated TD children who ate fresh water fish had a higher BMC than children who did not (11.0 µg/L vs. 9.9 µg/L; P = 0.03) as younger TD children (i.e., 2 ≤ age ≤4), (12.0 µg/L vs. 10.2 µg/L; P = 0.01). CONCLUSIONS: While these results cannot be used to assess early exposure at potentially more susceptible time period, our findings suggest that there is no significant association between manganese exposures and ASD case status in Jamaica. Our findings also indicate that BMC in Jamaican children resemble those of children in the developed world and are much lower than those in the developing countries.

Role of fruits, grains, and seafood consumption in blood cadmium concentrations of Jamaican children with and without Autism Spectrum Disorder.

Human exposure to cadmium has adverse effects on the nervous system. Utilizing data from 110 age- and sex-matched case-control pairs (220 children) ages 2-8 years in Kingston, Jamaica, we compared the 75th percentile of blood cadmium concentrations in children with and without Autism Spectrum Disorder (ASD). In both univariable and multivariable Quantile Regression Models that controlled for potential confounding factors, we did not find any significant differences between ASD cases and typically developing (TD) controls with respect to the 75th percentile of blood cadmium concentrations, (P > 0.22). However, we found a significantly higher 75th percentile of blood cadmium concentrations in TD Jamaican children who consumed shellfish (lobsters, crabs) (P <0.05), fried plantain (P <0.01), and boiled dumpling (P <0.01). We also observed that children living in Jamaica have an arithmetic mean blood cadmium concentration of 0.16µg/L which is similar to that of the children in developed countries and much lower than that of children in developing countries. Although our results do not support an association between blood cadmium concentrations and ASD, to our knowledge, this study is the first to report levels of blood cadmium in TD children as well as those with ASD in Jamaica.

Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder.

Arsenic is a toxic metalloid with known adverse effects on human health. Glutathione-S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play a major role in detoxification and metabolism of xenobiotics. We investigated the association between GST genotypes and whole blood arsenic concentrations (BASC) in Jamaican children with and without autism spectrum disorder (ASD). We used data from 100 ASD cases and their 1:1 age- and sex-matched typically developing (TD) controls (age 2-8 years) from Jamaica. Using log-transformed BASC as the dependent variable in a General Linear Model, we observed a significant interaction between GSTP1 and ASD case status while controlling for several confounding variables. However, for GSTT1 and GSTM1 we did not observe any significant associations with BASC. Our findings indicate that TD children who had the Ile/Ile or Ile/Val genotype for GSTP1 had a significantly higher geometric mean BASC than those with genotype Val/Val (3.67 µg/L vs. 2.69 µg/L, p < 0.01). Although, among the ASD cases, this difference was not statistically significant, the direction of the observed difference was consistent with that of the TD control children. These findings suggest a possible role of GSTP1 in the detoxification of arsenic.

Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders.

Mercury is a toxic metal shown to have harmful effects on human health. Several studies have reported high blood mercury concentrations as a risk factor for autism spectrum disorders (ASDs), while other studies have reported no such association. The goal of this study was to investigate the association between blood mercury concentrations in children and ASDs. Moreover, we investigated the role of seafood consumption in relation to blood mercury concentrations in Jamaican children. Based on data for 65 sex- and age-matched pairs (2-8 years), we used a General Linear Model to test whether there is an association between blood mercury concentrations and ASDs. After controlling for the child's frequency of seafood consumption, maternal age, and parental education, we did not find a significant difference (P = 0.61) between blood mercury concentrations and ASDs. However, in both cases and control groups, children who ate certain types of seafood (i.e., salt water fish, sardine, or mackerel fish) had significantly higher (all P < 0.05) geometric means blood mercury concentration which were about 3.5 times that of children living in the US or Canada. Our findings also indicate that Jamaican children with parents who both had education up to high school are at a higher risk of exposure to mercury compared to children with at least one parent who had education beyond high school. Based on our findings, we recommend additional education to Jamaican parents regarding potential hazards of elevated blood mercury concentrations, and its association with seafood consumption and type of seafood.

Population-based risk factors for elevated alanine aminotransferase in a South Texas Mexican-American population.

BACKGROUND AND AIMS: Elevated alanine aminotransferase (ALT >40 IU/mL) is a marker of liver injury but provides little insight into etiology. We aimed to identify and stratify risk factors associated with elevated ALT in a randomly selected population with a high prevalence of elevated ALT (39%), obesity (49%) and diabetes (30%). METHODS: Two machine learning methods, the support vector machine (SVM) and Bayesian logistic regression (BLR), were used to capture risk factors in a community cohort of 1532 adults from the Cameron County Hispanic Cohort (CCHC). A total of 28 predictor variables were used in the prediction models. The recently identified genetic marker rs738409 on the PNPLA3 gene was genotyped using the Sequenom iPLEX assay. RESULTS: The four major risk factors for elevated ALT were fasting plasma insulin level and insulin resistance, increased BMI and total body weight, plasma triglycerides and non-HDL cholesterol, and diastolic hypertension. In spite of the highly significant association of rs738409 in females, the role of rs738409 in the prediction model is minimal, compared to other epidemiological risk factors. Age and drug and alcohol consumption were not independent determinants of elevated ALT in this analysis. CONCLUSIONS: The risk factors most strongly associated with elevated ALT in this population are components of the metabolic syndrome and point to nonalcoholic fatty liver disease (NAFLD). This population-based model identifies the likely cause of liver disease without the requirement of individual pathological diagnosis of liver diseases. Use of such a model can greatly contribute to a population-based approach to prevention of liver disease.

PNPLA3 polymorphisms and liver aminotransferase levels in a Mexican American population.

PURPOSE: This study examined genetic associations of patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and liver aminotransferases in an extensively documented, randomly recruited Mexican American population at high risk of liver disease. METHODS: Two single nucleotide polymorphisms (SNP) in the PNPLA3 gene (i.e., rs738409 and rs2281135) were genotyped in 1532 individuals. Population stratification was corrected by the genotyping of 103 ancestry informative markers (AIMs) for Mexican Americans. RESULTS: Both PNPLA3 SNPs showed highly significant association with alanine aminotransferase (ALT) levels, but was also, in males, associated with aspartate aminotransferase (AST) levels. Haplotypic association test of the two SNPs suggested stronger genetic association with rs738409 than rs2281135. Obvious sex effects were observed: rs738409-sex interaction in ALT levels P = 8.37 x 10(-4); rs738409-sex interaction in AST levels P = 5.03 x 10(-3). CONCLUSIONS: This population study highlights a sex-specific association of PNPLA3 polymorphisms and elevated liver enzymes in a population-based study, independent of common pathological factors of the metabolic syndrome. The strong genetic association found in women ≤ 50 years old, but not in women > 50 years old, suggests that sex hormones may mediate the sex effect.

The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without Autism Spectrum Disorders.

Arsenic is a toxic metal with harmful effects on human health, particularly on cognitive function. Autism Spectrum Disorders (ASDs) are lifelong neurodevelopmental and behavioral disorders manifesting in infancy or early childhood. We used data from 130 children between 2 and 8 years (65 pairs of ASD cases with age- and sex-matched control), to compare the mean total blood arsenic concentrations in children with and without ASDs in Kingston, Jamaica. Based on univariable analysis, we observed a significant difference between ASD cases and controls (4.03 µg/L for cases vs. 4.48 µg/L for controls, P<0.01). In the final multivariable General Linear Model (GLM), after controlling for car ownership, maternal age, parental education levels, source of drinking water, consumption of "yam, sweet potato, or dasheen", "carrot or pumpkin", "callaloo, broccoli, or pak choi", cabbage, avocado, and the frequency of seafood consumption per week, we did not find a significant association between blood arsenic concentrations and ASD status (4.36 µg/L for cases vs. 4.65 µg/L for controls, P=0.23). Likewise, in a separate final multivariable GLM, we found that source of drinking water, eating avocado, and eating "callaloo, broccoli, or pak choi" was significantly associated with higher blood arsenic concentrations (all three P<0.05). Based on our findings, we recommend assessment of arsenic levels in water, fruits, and vegetables, as well as increased awareness among the Jamaican population regarding potential risks for various exposures to arsenic.

Maternal and paternal age are jointly associated with childhood autism in Jamaica.

Several studies have reported maternal and paternal age as risk factors for having a child with Autism Spectrum Disorder (ASD), yet the results remain inconsistent. We used data for 68 age- and sex-matched case-control pairs collected from Jamaica. Using Multivariate General Linear Models (MGLM) and controlling for parity, gestational age, and parental education, we found a significant (p < 0.0001) joint effect of parental ages on having children with ASD indicating an adjusted mean paternal age difference between cases and controls of [5.9 years; 95% CI (2.6, 9.1)] and a difference for maternal age of [6.5 years; 95% CI (4.0, 8.9)]. To avoid multicollinearity in logistic regression, we recommend joint modeling of parental ages as a vector of outcome variables using MGLM.

Gene by smoking interaction in hypertension: identification of a major quantitative trait locus on chromosome 15q for systolic blood pressure in Mexican-Americans.

OBJECTIVE: Our objective was to investigate the influence of gene by smoking (GxS) interaction on hypertension and blood pressure (BP) using genome-wide linkage analysis in Mexican-Americans, followed by single nucleotide polymorphism (SNP) fine mapping of candidate genes in the linked chromosomal region. METHODS: We used nonparametric methods to test for linkage of microsatellites with hypertension and BP measures in smokers, nonsmokers, and the combined group. To begin fine mapping of a major quantitative trait locus (QTL) for systolic blood pressure (SBP) on chromosome 15q that showed strong evidence for GxS interaction, we genotyped 55 SNPs in nine candidate genes for association studies using two population-based statistical methods. RESULTS: The strongest evidence for GxS interaction (P = 0.0004) was found for SBP on chromosome 15q, where a major QTL (LOD = 3.36) was identified only in nonsmokers. Follow-up studies identified three SNPs in three genes (ANPEP, IGF1R, and SLCO3A1) that showed associations with SBP only in nonsmokers, cumulatively accounting for a 7 mmHg increase in SBP. However, conditional linkage analyses that accounted for phenotypic effects of these SNPs only slightly reduced the original LOD score. CONCLUSION: The detection of a major QTL on chromosome 15q for SBP in nonsmokers indicates the presence of loci that influence BP via GxS interactions. However, identification of the genes that underlie such QTL effects remains a challenge. Although we found three candidate genes that showed significant associations with SBP in nonsmokers, further studies are required to identify the gene(s) that underlie the chromosome 15q QTL that influences SBP via GxS interactions.

Genome-wide distribution of ancestry in Mexican Americans.

Migrations to the new world brought together individuals from Europe, Africa and the Americans. Inter-mating between these migrant and indigenous populations led to the subsequent formation of new admixed populations, such as African and Latino Americans. These unprecedented events brought together genomes that had evolved independently on different continents for tens of thousands of years and presented new environmental challenges for the indigenous and migrant populations, as well as their offspring. These circumstances provided novel opportunities for natural selection to occur that could be reflected in deviations at specific locations from the genome-wide ancestry distribution. Here we present an analysis examining European, Native American and African ancestry based on 284 microsatellite markers in a study of Mexican Americans from the Family Blood Pressure Program. We identified two genomic regions where there was a significant decrement in African ancestry (at 2p25.1, p < 10(-8) and 9p24.1, p < 2 x 10(-5)) and one region with a significant increase in European ancestry (at 1p33, p < 2 x 10(-5)). These locations may harbor genes that have been subjected to natural selection after the ancestral mixing giving rise to Mexicans.

A genome-wide linkage scan for diabetic retinopathy susceptibility genes in Mexican Americans with type 2 diabetes from Starr County, Texas.

We conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least two diabetic siblings. The sample included 567 retinopathy case subjects comprising 282 affected sibling pairs. Retinopathy was classified as none, early nonproliferative, moderate-to-severe nonproliferative, or proliferative. Using 360 polymorphic markers (average spacing 9.4 cM), we conducted nonparametric linkage analysis followed by ordered-subset analysis (OSA) ranking families by average age of diabetes diagnosis. For any retinopathy, the highest LOD scores including all families were on chromosomes 3 (2.41 at 117 cM) and 12 (2.47 at 15.5). OSA logarithm of odds (LOD) scores >2 for any retinopathy occurred on chromosomes 12 (4.47 at 13.2 cM), 15 (3.65 at 100.6), and 20 (2.67 at 54.1). Scores >2 for either moderate-to-severe nonproliferative or proliferative retinopathy occurred on chromosomes 5 (2.53 at 11.2 cM), 6 (2.28 at 30.6), and 19 (2.21 at 100.6). Thus, unconditional linkage analysis revealed suggestive evidence of linkage with retinopathy on two chromosomes, whereas OSA revealed strong evidence of linkage on two chromosomes, and suggestive evidence on four. Candidate genes were identified in most implicated regions.