Publications by authors named "Megan L Grove"

107 Publications

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies.

Gut 2021 Jun 14. Epub 2021 Jun 14.

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.

Objective: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.

Method: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.

Results: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using . We identified a novel association between a host functional variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut , a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut and serum indolepropionate only among genetically lactase non-persistent individuals.

Conclusion: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.
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http://dx.doi.org/10.1136/gutjnl-2021-324053DOI Listing
June 2021

Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.

Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk.

Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.

Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.
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http://dx.doi.org/10.1002/alz.12333DOI Listing
May 2021

A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease.

Am J Physiol Lung Cell Mol Physiol 2021 Jul 28;321(1):L130-L143. Epub 2021 Apr 28.

Department of Health Sciences, University of Leicester, Leicester, United Kingdom.

Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant ( < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B () splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 (), a gene involved in regulating cell proliferation, were associated with COPD (both < 0.0001). The Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17-1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.
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http://dx.doi.org/10.1152/ajplung.00009.2021DOI Listing
July 2021

A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.

Am J Epidemiol 2021 Apr 16. Epub 2021 Apr 16.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
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http://dx.doi.org/10.1093/aje/kwab115DOI Listing
April 2021

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Eur Heart J 2021 05;42(18):1742-1756

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA.

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.

Methods And Results: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.

Conclusion: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehab107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244638PMC
May 2021

Associations of Metabolic Genes (, , ) and Blood Mercury Concentrations Differ in Jamaican Children with and without Autism Spectrum Disorder.

Int J Environ Res Public Health 2021 02 3;18(4). Epub 2021 Feb 3.

Department of Basic Medical Sciences, Mona Campus, The University of the West Indies, Kingston 7, Jamaica.

We investigated interactive roles of three metabolic glutathione S-transferase (GST) genes (, , and ) and autism spectrum disorder (ASD) status in relation to blood Hg concentrations (BHC) of Jamaican children. We used data from 266 children (2-8 years) with ASD and their 1:1 age- and sex-matched typically developing (TD) controls. After adjusting General Linear Models for child's age, socioeconomic status, consumption of leafy vegetables, fried plantain, canned fish, and the interaction between and , we found significant interactions between and ASD status in relation to BHC either in a co-dominant or dominant genetic model for ( < 0.001, = 0.007, respectively). In the co-dominant model for the Ile105Val polymorphism, geometric mean (GM) BHC in ASD cases with genotype Ile/Ile were significantly higher than in cases with the Ile/Val genotype (0.73 vs. 0.48 µg/L, = 0.01). In contrast, in TD controls with the Ile/Val genotype GM BHC were significantly higher than in those with the Ile/Ile genotype (0.72 vs. 0.49 µg/L, = 0.03) or the Val/Val genotype (0.72 vs. 0.51 µg/L, = 0.04). Although our findings are consistent with the role of in detoxification of Hg, replication in other populations is warranted.
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http://dx.doi.org/10.3390/ijerph18041377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913200PMC
February 2021

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 2021

Corrigendum to 'Association of sickle cell trait with measures of cognitive function and dementia in African Americans' Vol. 16 (2019), 100,201.

eNeurologicalSci 2020 Dec 12;21:100281. Epub 2020 Oct 12.

Aflac Cancer and Blood Disorder Center of Children's Healthcare of Atlanta, Emory Department of Pediatrics, Atlanta, GA, United States of America.

[This corrects the article DOI: 10.1016/j.ensci.2019.100201.].
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http://dx.doi.org/10.1016/j.ensci.2020.100281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719690PMC
December 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Interaction between a Mixture of Heavy Metals (Lead, Mercury, Arsenic, Cadmium, Manganese, Aluminum) and and in Relation to Autism Spectrum Disorder.

Res Autism Spectr Disord 2020 Nov 24;79. Epub 2020 Oct 24.

Louis A Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA.

Background: Exposure to many environmental chemicals, including metals, often does not occur in isolation, hence requires assessment of the associations between exposure to mixtures of chemicals and human health.

Objectives: To investigate associations of a metal mixture of lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) in children with autism spectrum disorder (ASD), additively or interactively with each of three glutathione S-transferase (GST) genes (, , and ).

Method: Using data from 266 case-control pairs of Jamaican children (2-8 years old), we fitted negative and positive generalized weighted quantile sum (gWQS) regression models to assess the aforementioned associations.

Results: Based on additive and interactive negative gWQS models adjusted for maternal age, parental education, child's parish, and seafood consumption, we found inverse associations of the overall mixture score with ASD [MOR (95% CI): 0.70 (0.49, 0.99); < 0.05) and [MOR (95%CI): 0.46 (0.25, 0.84); = 0.01], respectively. In an unadjusted negative gWQS model, we found a marginally significant interaction between and a mixture of three metals (Pb, Hg, and Mn) ( = 0.07) while the association was no longer significant after adjustment for the same covariates ( = 0.24).

Conclusions: Differences in diet between ASD and control groups may play a role in the inverse associations we found. The possible interactive association between Mn and in ASD based on gWQS is consistent with our previous reports. However, possible interaction of with Pb and Hg in ASD requires further investigation and replication.
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http://dx.doi.org/10.1016/j.rasd.2020.101681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664834PMC
November 2020

A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos.

Am J Hum Genet 2020 11 7;107(5):849-863. Epub 2020 Oct 7.

Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address:

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEV = 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675000PMC
November 2020

Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.

Genome Med 2020 09 28;12(1):84. Epub 2020 Sep 28.

McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.

Methods: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.

Results: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10), as well as the TFAM knockout methylation (P = 4.41 × 10) and expression (P = 4.30 × 10) studies.

Conclusions: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.
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http://dx.doi.org/10.1186/s13073-020-00778-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523322PMC
September 2020

Methylome-wide association study of central adiposity implicates genes involved in immune and endocrine systems.

Epigenomics 2020 09 9;12(17):1483-1499. Epub 2020 Sep 9.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African-American adults in the Atherosclerosis Risk in Communities study. We validated significantly associated cytosine-phosphate-guanine methylation sites (CpGs) among adults using the Women's Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near , ,  and that had not previously been associated with obesity-related traits.
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http://dx.doi.org/10.2217/epi-2019-0276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923253PMC
September 2020

Interaction of Blood Manganese Concentrations with GSTT1 in Relation to Autism Spectrum Disorder in Jamaican Children.

J Autism Dev Disord 2021 Jun;51(6):1953-1965

Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77054, USA.

Using data from 266 age- and sex-matched pairs of Jamaican children with autism spectrum disorder (ASD) and typically developing (TD) controls (2-8 years), we investigated whether glutathione S-transferase theta 1 (GSTT1) modifies the association between blood manganese concentrations (BMC) and ASD. After adjusting conditional logistic regression models for socioeconomic status and the interaction between GSTT1 and GSTP1 (glutathione S-transferase pi 1), using a recessive genetic model for GSTT1 and either a co-dominant or dominant model for GSTP1, the interaction between GSTT1 and BMC was significant (P = 0.02, P = 0.01, respectively). Compared to controls, ASD cases with GSTT1-DD genotype had 4.33 and 4.34 times higher odds of BMC > 12 vs. ≤ 8.3 μg/L, respectively. Replication in other populations is warranted.
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http://dx.doi.org/10.1007/s10803-020-04677-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936003PMC
June 2021

Association of Polychlorinated Biphenyls and Organochlorine Pesticides with Autism Spectrum Disorder in Jamaican Children.

Res Autism Spectr Disord 2020 Aug 18;76. Epub 2020 Jun 18.

Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

Background: Polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides are suspected to play a role in autism spectrum disorder (ASD).

Objectives: To investigate associations of PCBs and OC pesticides with ASD in Jamaican children and explore possible interaction between PCBs or OC pesticides with glutathione -transferase (GST) genes (, , ) in relation to ASD.

Methods: Participants included n=169 age- and sex-matched case-control pairs of Jamaican children 2-8 years old. Socioeconomic status and food frequency data were self-reported by the parents/guardians. Blood from each participant was analyzed for 100 PCB congeners and 17 OC pesticides and genotyped for three GST genes. PCBs and OC pesticides concentrations below the limit of detection (LoD) were replaced with (LoD/√2). We used conditional logistic regression (CLR) models to assess associations of PCBs and OC pesticides with ASD, individually or interactively with GST genes (, , ).

Results: We found inverse associations of PCB-153 [adjusted MOR (95% CI) = 0.44 (0.23-0.86)] and PCB-180 [adjusted MOR (95% CI) = 0.52 (0.28-0.95)] with ASD. When adjusted for covariates in a CLR the interaction between and PCB-153 became significant ( < 0.01).

Discussion: Differences in diet between ASD and typically developing control groups may play a role in the observed findings of lower concentrations of PCB-153 and PCB-180 in individuals with ASD than in controls. Considering the limited sample size and high proportion of concentrations below the LoD, these results should be interpreted with caution but warrant further investigation into associations of PCBs and OC pesticides with ASD.
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http://dx.doi.org/10.1016/j.rasd.2020.101587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357892PMC
August 2020

Mitochondrial DNA Copy Number and Incident Heart Failure: The Atherosclerosis Risk in Communities (ARIC) Study.

Circulation 2020 06 1;141(22):1823-1825. Epub 2020 Jun 1.

Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Bloomberg School of Public Health (Y.S.H., D.Z., K.M., E.G.), Johns Hopkins University, Baltimore, MD.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295435PMC
June 2020

Serum sphingolipids and incident diabetes in a US population with high diabetes burden: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Am J Clin Nutr 2020 07;112(1):57-65

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies.

Objectives: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort.

Methods: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores.

Results: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1 = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1 = 3.15; 95% CI: 1.75, 5.67; P-trend <0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1 = 1.98; 95% CI: 1.09, 3.59; P-trend = 0.031).

Conclusions: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.
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http://dx.doi.org/10.1093/ajcn/nqaa114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326587PMC
July 2020

Analysis of putative cis-regulatory elements regulating blood pressure variation.

Hum Mol Genet 2020 07;29(11):1922-1932

Department of Genetic Medicine, McKusick-Nathans Institute, Baltimore, MD 21205, USA.

Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of 'expressed' genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.
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http://dx.doi.org/10.1093/hmg/ddaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372556PMC
July 2020

Evaluation of mitochondrial DNA copy number estimation techniques.

PLoS One 2020 31;15(1):e0228166. Epub 2020 Jan 31.

Department of Genetic Medicine, McKusick-Nathans Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.

Mitochondrial DNA copy number (mtDNA-CN), a measure of the number of mitochondrial genomes per cell, is a minimally invasive proxy measure for mitochondrial function and has been associated with several aging-related diseases. Although quantitative real-time PCR (qPCR) is the current gold standard method for measuring mtDNA-CN, mtDNA-CN can also be measured from genotyping microarray probe intensities and DNA sequencing read counts. To conduct a comprehensive examination on the performance of these methods, we use known mtDNA-CN correlates (age, sex, white blood cell count, Duffy locus genotype, incident cardiovascular disease) to evaluate mtDNA-CN calculated from qPCR, two microarray platforms, as well as whole genome (WGS) and whole exome sequence (WES) data across 1,085 participants from the Atherosclerosis Risk in Communities (ARIC) study and 3,489 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). We observe mtDNA-CN derived from WGS data is significantly more associated with known correlates compared to all other methods (p < 0.001). Additionally, mtDNA-CN measured from WGS is on average more significantly associated with traits by 5.6 orders of magnitude and has effect size estimates 5.8 times more extreme than the current gold standard of qPCR. We further investigated the role of DNA extraction method on mtDNA-CN estimate reproducibility and found mtDNA-CN estimated from cell lysate is significantly less variable than traditional phenol-chloroform-isoamyl alcohol (p = 5.44x10-4) and silica-based column selection (p = 2.82x10-7). In conclusion, we recommend the field moves towards more accurate methods for mtDNA-CN, as well as re-analyze trait associations as more WGS data becomes available from larger initiatives such as TOPMed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228166PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994099PMC
April 2020

Deletion Exaggerates Kidney Injury in Experimental Mouse Models and Confers the Protective Effect of Cruciferous Vegetables in Mice and Humans.

J Am Soc Nephrol 2020 01 14;31(1):102-116. Epub 2019 Nov 14.

Division of Nephrology, Department of Medicine and

Background: encodes glutathione S-transferase -1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study.

Methods: We generated a knockout mouse line to study its role in a CKD model (involving subtotal nephrectomy) and a hypertension model (induced by angiotensin II). We examined the effect of intake of cruciferous vegetables and genotypes on kidney disease in mice as well as in human ARIC study participants. We also examined the importance of superoxide in the mediating pathways and of hematopoietic on renal inflammation.

Results: knockout mice displayed increased oxidative stress, kidney injury, and inflammation in both models. The central mechanism for kidney injury is likely mediated by oxidative stress, because treatment with Tempol, an superoxide dismutase mimetic, rescued kidney injury in knockout mice without lowering BP. Bone marrow crosstransplantation revealed that deletion in the parenchyma, and not in bone marrow-derived cells, drives renal inflammation. Furthermore, supplementation with cruciferous broccoli powder rich in the precursor to antioxidant-activating sulforaphane significantly ameliorated kidney injury in knockout, but not wild-type mice. Similarly, among humans (ARIC study participants), high consumption of cruciferous vegetables was associated with fewer kidney failure events compared with low consumption, but this association was observed primarily in participants homozygous for the deletion variant.

Conclusions: Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.
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http://dx.doi.org/10.1681/ASN.2019050449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935006PMC
January 2020

Epigenetic Age Acceleration and Cognitive Function in African American Adults in Midlife: The Atherosclerosis Risk in Communities Study.

J Gerontol A Biol Sci Med Sci 2020 02;75(3):473-480

Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, UK.

Methylation levels measured at defined sites across the genome have recently been shown to be correlated with an individual's chronological age. Age acceleration, or the difference between age estimated from DNA methylation status and chronological age, has been proposed as a novel biomarker of aging. In this study, the cross-sectional association between two different measures of age acceleration and cognitive function was investigated using whole blood samples from 2,157 African American participants 47-70 years of age in the population-based Atherosclerosis Risk in Communities (ARIC) Study. Cognition was evaluated using three domain-specific tests. A significant inverse association between a 1-year increase in age acceleration calculated using a blood-based age predictor and scores on the Word Fluency Test was found using a general linear model adjusted for chronological age, gender, and years of education (β = -0.140 words; p = .001) and after adding other potential confounding variables (β = -0.104 words, p = .023). The results were replicated in 1,670 European participants in the Generation Scotland: Scottish Family Health Study (fully adjusted model: β = -0.199 words; p = .034). A significant association was also identified in a trans-ethnic meta-analysis across cohorts that included an additional 708 European American ARIC study participants (fully adjusted model: β = -0.110 words, p = .003). There were no associations found using an estimate of age acceleration derived from multiple tissues. These findings provide evidence that age acceleration is a correlate of performance on a test of verbal fluency in middle-aged adults.
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http://dx.doi.org/10.1093/gerona/glz245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328191PMC
February 2020

Perinatal Factors Associated with Autism Spectrum Disorder in Jamaican Children.

J Autism Dev Disord 2020 Sep;50(9):3341-3357

Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

Mode of delivery, preterm birth, and low birth weight (LBW) are hypothesized to be associated with autism spectrum disorder (ASD) in the offspring. Using data from 343 ASD cases (2-8 years) and their age- and sex-matched typically developing controls in Jamaica we investigated these hypotheses. Our statistical analyses revealed that the parish of residence could modify the association between cesarean delivery and ASD, with a difference found in this relationship in Kingston parish [matched odds ratio (MOR) (95% confidence interval (CI)) 2.30 (1.17-4.53)] and other parishes [MOR (95% CI) 0.87 (0.48-1.59)]. Although the associations of LBW and preterm birth with ASD were not significant, we observed a significant interaction between LBW and the household socioeconomic status. These findings require replication.
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http://dx.doi.org/10.1007/s10803-019-04229-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080579PMC
September 2020

Hypertensive APOL1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers.

PLoS One 2019 18;14(9):e0221957. Epub 2019 Sep 18.

Section of Nephrology, University of Chicago, Chicago, Illinois, United States of America.

Background: Hypertension (HTN) disproportionately affects African Americans (AAs), who respond better to thiazide diuretics than other antihypertensives. Variants of the APOL1 gene found in AAs are associated with a higher rate of kidney disease and play a complex role in cardiovascular disease.

Methods: AA subjects from four HTN trials (n = 961) (GERA1, GERA2, PEAR1, and PEAR2) were evaluated for blood pressure (BP) response based on APOL1 genotype after 4-9 weeks of monotherapy with thiazides, beta blockers, or candesartan. APOL1 G1 and G2 variants were determined by direct sequencing or imputation.

Results: Baseline systolic BP (SBP) and diastolic BP (DBP) levels did not differ based on APOL1 genotype. Subjects with 1-2 APOL1 risk alleles had a greater SBP response to candesartan (-12.2 +/- 1.2 vs -7.5 +/- 1.8 mmHg, p = 0.03; GERA2), and a greater decline in albuminuria with candesartan (-8.3 +/- 3.1 vs +3.7 +/- 4.3 mg/day, p = 0.02). APOL1 genotype did not associate with BP response to thiazides or beta blockers. GWAS was performed to determine associations with BP response to candesartan depending on APOL1 genotype. While no SNPs reached genome wide significance, SNP rs10113352, intronic in CSMD1, predicted greater office SBP response to candesartan (p = 3.7 x 10-7) in those with 1-2 risk alleles, while SNP rs286856, intronic in DPP6, predicted greater office SBP response (p = 3.2 x 10-7) in those with 0 risk alleles.

Conclusions: Hypertensive AAs without overt kidney disease who carry 1 or more APOL1 risk variants have a greater BP and albuminuria reduction in response to candesartan therapy. BP response to thiazides or beta blockers did not differ by APOL1 genotype. Future studies confirming this initial finding in an independent cohort are required.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221957PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750571PMC
March 2020

Association of sickle cell trait with measures of cognitive function and dementia in African Americans.

eNeurologicalSci 2019 Sep 22;16:100201. Epub 2019 Jul 22.

Aflac Cancer and Blood Disorder Center of Children's Healthcare of Atlanta, Emory Department of Pediatrics, Atlanta, GA, United States of America.

Objective: The incidence and prevalence of cognitive decline and dementia are significantly higher among African Americans compared with non-Hispanic Whites. The aim of this study was to determine whether inheritance of the sickle cell trait (SCT) i.e. heterozygosity for the sickle cell mutation increases the risk of cognitive decline or dementia Among African Americans.

Methods: We studied African American participants enrolled in the Atherosclerosis Risk in Communities study. SCT genotype at baseline and outcome data from cognitive assessments at visits 2, 4 and 5, and an MRI performed at visit 5 were analyzed for the association between SCT and risk of cognitive impairment and/or dementia.

Results: There was no significant difference in risk factors profile between participants with SCT ( = 176) and those without SCT ( = 2532). SCT was not independently associated with a higher prevalence of global or domain-specific cognitive impairment at baseline or with more rapid cognitive decline. Participants with SCT had slightly lower incidence of dementia (HR = 0.63 [0.38, 1.05]). On the other hand, SCT seems to interact with the apolipoprotein E ε4 risk allele resulting in poor performance on digit symbol substitution test at baseline (z-score = -0.08, P = 0.05) and over time (z-score = -0.12, P = 0.04); and with diabetes mellitus leading to a moderately increased risk of dementia (HR = 2.06 [0.89, 4.78], P = 0.01).

Conclusions: SCT was not an independent risk factor for prevalence or incidence of cognitive decline or dementia, although it may interact with and modify other putative risk factors for cognitive decline and dementia.
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http://dx.doi.org/10.1016/j.ensci.2019.100201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661502PMC
September 2019

Concentrations of Lead, Mercury, Arsenic, Cadmium, Manganese, and Aluminum in Blood of Romanian Children Suspected of Having Autism Spectrum Disorder.

Int J Environ Res Public Health 2019 06 28;16(13). Epub 2019 Jun 28.

Department of Child and Adolescent Psychiatry, University of Medicine and Pharmacy of Carol Davila, Psychiatry Clinical Hospital Alexandru Obregia, Bucharest, sector 4, 041914, Romania.

Environmental exposure to lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) has been associated with neurodevelopmental disorders including autism spectrum disorder (ASD). We conducted a pilot study during May 2015-May 2107 to estimate blood concentrations of six metals (Pb, Hg, As, Cd, Mn, and Al) and identify their associated factors for children with ASD or suspected of having ASD in Romania. Sixty children, age 2-8 years, were administered versions of ADOS or ADI-R translated from English to Romanian. After assessment, 2-3 mL of blood was obtained and analyzed for the concentrations of the six metals. The mean age of children was 51.9 months and about 90% were male. More than half (65%) of the children were born in Bucharest. Over 90% of concentrations of As and Cd were below limits of detection. Geometric mean concentrations of Pb, Mn, Al, and Hg were 1.14 μg/dL, 10.84 μg/L, 14.44 μg/L, and 0.35 μg/L, respectively. Multivariable linear regression analysis revealed that children who were female, had less educated parents, exhibited pica, and ate cold breakfast (e.g., cereal), watermelon, and lamb had significantly higher concentrations of Pb compared to their respective referent categories (all < 0.05 except for eating lamb, which was marginally significant, = 0.053). Although this is the first study that provides data on concentrations of the six metals for Romanian children with ASD, the findings from this study could be useful for designing future epidemiologic studies for investigating the role of these six metals in ASD in Romanian children.
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http://dx.doi.org/10.3390/ijerph16132303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651707PMC
June 2019

Multiple variant enhancers modulate its cardiac gene expression and the QT interval.

Proc Natl Acad Sci U S A 2019 05 8;116(22):10636-10645. Epub 2019 May 8.

Center for Human Genetics and Genomics, New York University School of Medicine, New York, NY 10016;

The rationale for genome-wide association study (GWAS) results is sequence variation in -regulatory elements (CREs) modulating a target gene's expression as the major cause of trait variation. To understand the complete molecular landscape of one of these GWAS loci, we performed in vitro reporter screens in cardiomyocyte cell lines for CREs overlapping nearly all common variants associated with any of five independent QT interval (QTi)-associated GWAS hits at the - locus. We identified 13 causal CRE variants using allelic reporter activity, cardiomyocyte nuclear extract-based binding assays, overlap with human cardiac tissue DNaseI hypersensitive regions, and predicted impact of sequence variants on DNaseI sensitivity. Our analyses identified at least one high-confidence causal CRE variant for each of the five sentinel hits that could collectively predict cardiac gene expression and QTi association. Although all 13 variants could explain gene expression, the highest statistical significance was obtained with seven variants (inclusive of the five above). Thus, multiple, causal, mutually associated CRE variants can underlie GWAS signals.
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http://dx.doi.org/10.1073/pnas.1808734116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561183PMC
May 2019

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

Biom J 2019 07 6;61(4):934-954. Epub 2019 May 6.

The University of Texas Health Science Center at Houston, Houston, TX, USA.

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.
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http://dx.doi.org/10.1002/bimj.201800259DOI Listing
July 2019

Interaction between manganese and in relation to autism spectrum disorder while controlling for exposure to mixture of lead, mercury, arsenic, and cadmium.

Res Autism Spectr Disord 2018 Nov 5;55:50-63. Epub 2018 Sep 5.

Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

Background: We previously reported a significant interactive association between polymorphisms of and blood manganese concentrations (BMC) with autism spectrum disorder (ASD) in Jamaican children. In this paper, we investigate the same interactive association with ASD while adjusting for the mixture of four metals (lead, mercury, cadmium, and arsenic).

Method: We used data from 163 case-control pairs of children 2-8 years of age from our autism project in Jamaica, in which we collected blood for heavy metals analysis at enrollment. To minimize potential multicollinearity between concentrations of the four metals, we generated a mixture index using generalized weighted quantile sum regression, which was used in conditional logistic regression models to control for the four metals while assessing the interactive association between and BMC with ASD.

Results: Similar to the findings we reported previously, we found that in co-dominant and dominant models for among children with the Ile/Ile genotype, those with BMC > 12μg/L had 4.6 and 4.27 times higher odds of ASD compared to those with BMC < 12μg/L (adjusted Matched Odds Ratio (MOR) = 4.6, 95% CI: 1.21 - 17.42 and adjusted MOR = 4.27, 95% CI: 1.15 - 15.85, respectively). In the co-dominant model, for children with the Ile/Val and Val/Val genotypes, the adjusted MORs were 1.26 (95% CI: 0.32, 5.01) and 0.26 (95% CI: 0.05, 1.42), respectively.

Conclusions: After adjusting for the mixture of four metals, the interactive association of BMC and with ASD remained significant with similar magnitude of associations. Results should be interpreted cautiously.
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http://dx.doi.org/10.1016/j.rasd.2018.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434704PMC
November 2018