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39 results on '"Murray JC"'

1. Risk of pre-eclampsia in patients with a maternal genetic predisposition to common medical conditions: a case-control study.

Author

Gray KJ, Kovacheva VP, Mirzakhani H, Bjonnes AC, Almoguera B, Wilson ML, Ingles SA, Lockwood CJ, Hakonarson H, McElrath TF, Murray JC, Norwitz ER, Karumanchi SA, Bateman BT, Keating BJ, and Saxena R

Subjects
Adult, Body Mass Index, Case-Control Studies, Europe, Female, Genome-Wide Association Study, Humans, Hypertension, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors, United States, White People, Young Adult, Genetic Predisposition to Disease, Pre-Eclampsia genetics
Abstract

Objective: To assess whether women with a genetic predisposition to medical conditions known to increase pre-eclampsia risk have an increased risk of pre-eclampsia in pregnancy., Design: Case-control study., Setting and Population: Pre-eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene-centric array., Methods: Significant single-nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre-eclampsia. Odds of pre-eclampsia were compared across quartiles of the genetic instrument and evaluated for significance., Main Outcome Measures: Genetic predisposition to medical conditions and relationship with pre-eclampsia., Results: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre-eclampsia (DBP, overall OR 1.11, 95% CI 1.01-1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00-1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82-0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset pre-eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08-1.56, P = 0.005). For other traits, there was no evidence of an association., Conclusions: These results suggest that the underlying genetic architecture of pre-eclampsia may be shared with other disorders, specifically hypertension and obesity., Tweetable Abstract: A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre-eclampsia., (© 2020 John Wiley & Sons Ltd.)

Published
2021
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2. Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios.

Author

Bishop MR, Diaz Perez KK, Sun M, Ho S, Chopra P, Mukhopadhyay N, Hetmanski JB, Taub MA, Moreno-Uribe LM, Valencia-Ramirez LC, Restrepo Muñeton CP, Wehby G, Hecht JT, Deleyiannis F, Weinberg SM, Wu-Chou YH, Chen PK, Brand H, Epstein MP, Ruczinski I, Murray JC, Beaty TH, Feingold E, Lipinski RJ, Cutler DJ, Marazita ML, and Leslie EJ

Subjects
Asian People genetics, Female, Genome-Wide Association Study methods, Humans, Male, Polymorphism, Single Nucleotide genetics, White People genetics, Whole Genome Sequencing methods, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease genetics, Mutation genetics
Abstract

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2020
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3. CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer.

Author

Selvanathan A, Nixon CY, Zhu Y, Scietti L, Forneris F, Uribe LMM, Lidral AC, Jezewski PA, Mulliken JB, Murray JC, Buckley MF, Cox TC, and Roscioli T

Subjects
Brain pathology, Cleft Lip epidemiology, Cleft Lip pathology, Cleft Palate epidemiology, Cleft Palate pathology, Female, Genetic Counseling, Germ-Line Mutation genetics, Humans, Male, Pedigree, Phenotype, Stomach Neoplasms epidemiology, Stomach Neoplasms pathology, Antigens, CD genetics, Brain abnormalities, Cadherins genetics, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease, Stomach Neoplasms genetics
Abstract

Pathogenic variants in CDH1 , encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least 'likely pathogenic', and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.

Published
2020
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4. Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21.

Author

Mukhopadhyay N, Bishop M, Mortillo M, Chopra P, Hetmanski JB, Taub MA, Moreno LM, Valencia-Ramirez LC, Restrepo C, Wehby GL, Hecht JT, Deleyiannis F, Butali A, Weinberg SM, Beaty TH, Murray JC, Leslie EJ, Feingold E, and Marazita ML

Subjects
Child, Colombia, Female, Genome-Wide Association Study, Genotype, Humans, Male, Chromosomes, Human, Pair 21 genetics, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People genetics, Whole Genome Sequencing methods
Abstract

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.

Published
2020
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5. Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans.

Author

Cox TC, Lidral AC, McCoy JC, Liu H, Cox LL, Zhu Y, Anderson RD, Moreno Uribe LM, Anand D, Deng M, Richter CT, Nidey NL, Standley JM, Blue EE, Chong JX, Smith JD, Kirk EP, Venselaar H, Krahn KN, van Bokhoven H, Zhou H, Cornell RA, Glass IA, Bamshad MJ, Nickerson DA, Murray JC, Lachke SA, Thompson TB, Buckley MF, and Roscioli T

Subjects
Alleles, Amino Acid Substitution, Bone Morphogenetic Proteins antagonists & inhibitors, Cell Line, Computational Biology methods, Follistatin chemistry, Genomics methods, Growth Differentiation Factors antagonists & inhibitors, Humans, Models, Molecular, Pedigree, Protein Conformation, Exome Sequencing, Bone Morphogenetic Proteins genetics, Cleft Lip diagnosis, Cleft Lip genetics, Follistatin metabolism, Genetic Association Studies methods, Genetic Predisposition to Disease, Growth Differentiation Factors genetics, Mutation
Abstract

Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development., (© 2019 Wiley Periodicals, Inc.)

Published
2019
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6. Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts.

Author

Shaffer JR, LeClair J, Carlson JC, Feingold E, Buxó CJ, Christensen K, Deleyiannis FWB, Field LL, Hecht JT, Moreno L, Orioli IM, Padilla C, Vieira AR, Wehby GL, Murray JC, Weinberg SM, Marazita ML, and Leslie EJ

Subjects
Alleles, Enhancer Elements, Genetic, Genome-Wide Association Study, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, Brain abnormalities, Cleft Lip diagnosis, Cleft Lip genetics, Cleft Palate diagnosis, Cleft Palate genetics, Genetic Association Studies methods, Genetic Predisposition to Disease, Genetic Variation, Regulatory Sequences, Nucleic Acid
Abstract

Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the "missing" heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01-1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value = .0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value = .001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs., (© 2018 Wiley Periodicals, Inc.)

Published
2019
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7. Inferring disease risk genes from sequencing data in multiplex pedigrees through sharing of rare variants.

Author

Bureau A, Begum F, Taub MA, Hetmanski JB, Parker MM, Albacha-Hejazi H, Scott AF, Murray JC, Marazita ML, Bailey-Wilson JE, Beaty TH, and Ruczinski I

Subjects
Cleft Palate genetics, Computer Simulation, Exome genetics, Genetic Heterogeneity, Haplotypes genetics, Humans, Models, Genetic, Phenotype, Probability, Risk Factors, Exome Sequencing, Genetic Predisposition to Disease, Genetic Variation, Pedigree, Sequence Analysis, DNA
Abstract

We previously demonstrated how sharing of rare variants (RVs) in distant affected relatives can be used to identify variants causing a complex and heterogeneous disease. This approach tested whether single RVs were shared by all sequenced affected family members. However, as with other study designs, joint analysis of several RVs (e.g., within genes) is sometimes required to obtain sufficient statistical power. Further, phenocopies can lead to false negatives for some causal RVs if complete sharing among affected is required. Here, we extend our methodology (Rare Variant Sharing, RVS) to address these issues. Specifically, we introduce gene-based analyses, a partial sharing test based on RV sharing probabilities for subsets of affected relatives and a haplotype-based RV definition. RVS also has the desirable feature of not requiring external estimates of variant frequency or control samples, provides functionality to assess and address violations of key assumptions, and is available as open source software for genome-wide analysis. Simulations including phenocopies, based on the families of an oral cleft study, revealed the partial and complete sharing versions of RVS achieved similar statistical power compared with alternative methods (RareIBD and the Gene-Based Segregation Test), and had superior power compared with the pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) linkage statistic. In studies of multiplex cleft families, analysis of rare single nucleotide variants in the exome of 151 affected relatives from 54 families revealed no significant excess sharing in any one gene, but highlighted different patterns of sharing revealed by the complete and partial sharing tests., (© 2018 Wiley Periodicals, Inc.)

Published
2019
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8. Genome-wide interaction studies identify sex-specific risk alleles for nonsyndromic orofacial clefts.

Author

Carlson JC, Nidey NL, Butali A, Buxo CJ, Christensen K, Deleyiannis FW, Hecht JT, Field LL, Moreno-Uribe LM, Orioli IM, Poletta FA, Padilla C, Vieira AR, Weinberg SM, Wehby GL, Feingold E, Murray JC, Marazita ML, and Leslie EJ

Subjects
Case-Control Studies, Epistasis, Genetic, Female, Gene Frequency genetics, Genetic Loci, Humans, Male, Models, Genetic, Polymorphism, Single Nucleotide, Risk Factors, Alleles, Brain abnormalities, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Sex Characteristics
Abstract

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G × S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test ( p < 1.00 × 10 -5 ) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results ( p < 1.00 × 10 -5 ) for the joint test, we observed one genome-wide significant G × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 -9 ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects., (© 2018 Wiley Periodicals, Inc.)

Published
2018
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9. Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1 .

Author

Gray KJ, Kovacheva VP, Mirzakhani H, Bjonnes AC, Almoguera B, DeWan AT, Triche EW, Saftlas AF, Hoh J, Bodian DL, Klein E, Huddleston KC, Ingles SA, Lockwood CJ, Hakonarson H, McElrath TF, Murray JC, Wilson ML, Norwitz ER, Karumanchi SA, Bateman BT, Keating BJ, and Saxena R

Subjects
Adult, Case-Control Studies, Europe epidemiology, Female, Genotype, Humans, Incidence, Odds Ratio, Phenotype, Pre-Eclampsia epidemiology, Pregnancy, United States epidemiology, Blood Pressure physiology, DNA genetics, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide, Pre-Eclampsia genetics, Rho Guanine Nucleotide Exchange Factors genetics
Abstract

The genetic susceptibility to preeclampsia, a pregnancy-specific complication with significant maternal and fetal morbidity, has been poorly characterized. To identify maternal genes associated with preeclampsia risk, we assembled 498 cases and 1864 controls of European ancestry from preeclampsia case-control collections in 5 different US sites (with additional matched population controls), genotyped samples on a cardiovascular gene-centric array composed of variants from ≈2000 genes selected based on prior genetic studies of cardiovascular and metabolic diseases and performed case-control genetic association analysis on 27 429 variants passing quality control. In silico replication testing of 9 lead signals with P <10 - 4 was performed in independent European samples from the SOPHIA (Study of Pregnancy Hypertension in Iowa) and Inova cohorts (212 cases, 456 controls). Multiethnic assessment of lead signals was then performed in samples of black (26 cases, 136 controls), Hispanic (132 cases, 468 controls), and East Asian (9 cases, 80 controls) ancestry. Multiethnic meta-analysis (877 cases, 3004 controls) revealed a study-wide statistically significant association of the rs9478812 variant in the pleiotropic PLEKHG1 gene (odds ratio, 1.40 [1.23-1.60]; P meta =5.90×10 -7 ). The rs9478812 effect was even stronger in the subset of European cases with known early-onset preeclampsia (236 cases diagnosed <37 weeks, 1864 controls; odds ratio, 1.59 [1.27-1.98]; P =4.01×10 -5 ). PLEKHG1 variants have previously been implicated in genome-wide association studies of blood pressure, body weight, and neurological disorders. Although larger studies are required to further define maternal preeclampsia heritability, this study identifies a novel maternal risk locus for further investigation., (© 2018 American Heart Association, Inc.)

Published
2018
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10. Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.

Author

Huusko JM, Karjalainen MK, Graham BE, Zhang G, Farrow EG, Miller NA, Jacobsson B, Eidem HR, Murray JC, Bedell B, Breheny P, Brown NW, Bødker FL, Litterman NK, Jiang PP, Russell L, Hinds DA, Hu Y, Rokas A, Teramo K, Christensen K, Williams SM, Rämet M, Kingsmore SF, Ryckman KK, Hallman M, and Muglia LJ

Subjects
Adenosine Diphosphate chemistry, Adenosine Diphosphate metabolism, Case-Control Studies, Cell Line, Exome genetics, Female, Fibroblasts, Finland, Genome-Wide Association Study, HSP70 Heat-Shock Proteins chemistry, HSP70 Heat-Shock Proteins metabolism, Humans, Infant, Newborn, Male, Models, Molecular, Phosphorylation genetics, Polymorphism, Single Nucleotide, Pregnancy, Receptors, Glucocorticoid metabolism, Recurrence, Risk Factors, Signal Transduction genetics, Exome Sequencing, Genetic Predisposition to Disease, HSP70 Heat-Shock Proteins genetics, Premature Birth genetics
Abstract

Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2-4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB., Competing Interests: The 23andMe authors are employees of and hold stock or stock options in 23andMe, Inc.

Published
2018
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11. Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.

Author

Cox LL, Cox TC, Moreno Uribe LM, Zhu Y, Richter CT, Nidey N, Standley JM, Deng M, Blue E, Chong JX, Yang Y, Carstens RP, Anand D, Lachke SA, Smith JD, Dorschner MO, Bedell B, Kirk E, Hing AV, Venselaar H, Valencia-Ramirez LC, Bamshad MJ, Glass IA, Cooper JA, Haan E, Nickerson DA, van Bokhoven H, Zhou H, Krahn KN, Buckley MF, Murray JC, Lidral AC, and Roscioli T

Subjects
Alleles, Amino Acid Sequence, Animals, Biotinylation, Epithelium metabolism, Epithelium pathology, Female, Gene Deletion, Humans, Infant, Infant, Newborn, Male, Mice, Palate pathology, Pedigree, Syndrome, Exome Sequencing, Delta Catenin, Cadherins genetics, Catenins genetics, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease, Mutation genetics
Abstract

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14% of multi-affected families and 2% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)

Published
2018
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12. Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations.

Author

Gowans LJ, Adeyemo WL, Eshete M, Mossey PA, Busch T, Aregbesola B, Donkor P, Arthur FK, Bello SA, Martinez A, Li M, Augustine-Akpan EA, Deressa W, Twumasi P, Olutayo J, Deribew M, Agbenorku P, Oti AA, Braimah R, Plange-Rhule G, Gesses M, Obiri-Yeboah S, Oseni GO, Olaitan PB, Abdur-Rahman L, Abate F, Hailu T, Gravem P, Ogunlewe MO, Buxó CJ, Marazita ML, Adeyemo AA, Murray JC, and Butali A

Subjects
Ethiopia epidemiology, Female, Genetic Loci genetics, Genetic Markers genetics, Genome-Wide Association Study, Ghana epidemiology, Humans, Male, Nigeria epidemiology, Polymorphism, Single Nucleotide genetics, Sequence Analysis, DNA, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease genetics
Abstract

Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10(-3)), 8q24 (rs987525, P = 1.22 × 10(-3)), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29 In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population., Competing Interests: The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article., (© International & American Associations for Dental Research 2016.)

Published
2016
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13. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S, Czajkowski J, Esko T, Fall T, Kilpeläinen TO, Lu Y, Mägi R, Mihailov E, Pers TH, Rüeger S, Teumer A, Ehret GB, Ferreira T, Heard-Costa NL, Karjalainen J, Lagou V, Mahajan A, Neinast MD, Prokopenko I, Simino J, Teslovich TM, Jansen R, Westra HJ, White CC, Absher D, Ahluwalia TS, Ahmad S, Albrecht E, Alves AC, Bragg-Gresham JL, de Craen AJ, Bis JC, Bonnefond A, Boucher G, Cadby G, Cheng YC, Chiang CW, Delgado G, Demirkan A, Dueker N, Eklund N, Eiriksdottir G, Eriksson J, Feenstra B, Fischer K, Frau F, Galesloot TE, Geller F, Goel A, Gorski M, Grammer TB, Gustafsson S, Haitjema S, Hottenga JJ, Huffman JE, Jackson AU, Jacobs KB, Johansson Å, Kaakinen M, Kleber ME, Lahti J, Mateo Leach I, Lehne B, Liu Y, Lo KS, Lorentzon M, Luan J, Madden PA, Mangino M, McKnight B, Medina-Gomez C, Monda KL, Montasser ME, Müller G, Müller-Nurasyid M, Nolte IM, Panoutsopoulou K, Pascoe L, Paternoster L, Rayner NW, Renström F, Rizzi F, Rose LM, Ryan KA, Salo P, Sanna S, Scharnagl H, Shi J, Smith AV, Southam L, Stančáková A, Steinthorsdottir V, Strawbridge RJ, Sung YJ, Tachmazidou I, Tanaka T, Thorleifsson G, Trompet S, Pervjakova N, Tyrer JP, Vandenput L, van der Laan SW, van der Velde N, van Setten J, van Vliet-Ostaptchouk JV, Verweij N, Vlachopoulou E, Waite LL, Wang SR, Wang Z, Wild SH, Willenborg C, Wilson JF, Wong A, Yang J, Yengo L, Yerges-Armstrong LM, Yu L, Zhang W, Zhao JH, Andersson EA, Bakker SJ, Baldassarre D, Banasik K, Barcella M, Barlassina C, Bellis C, Benaglio P, Blangero J, Blüher M, Bonnet F, Bonnycastle LL, Boyd HA, Bruinenberg M, Buchman AS, Campbell H, Chen YD, Chines PS, Claudi-Boehm S, Cole J, Collins FS, de Geus EJ, de Groot LC, Dimitriou M, Duan J, Enroth S, Eury E, Farmaki AE, Forouhi NG, Friedrich N, Gejman PV, Gigante B, Glorioso N, Go AS, Gottesman O, Gräßler J, Grallert H, Grarup N, Gu YM, Broer L, Ham AC, Hansen T, Harris TB, Hartman CA, Hassinen M, Hastie N, Hattersley AT, Heath AC, Henders AK, Hernandez D, Hillege H, Holmen O, Hovingh KG, Hui J, Husemoen LL, Hutri-Kähönen N, Hysi PG, Illig T, De Jager PL, Jalilzadeh S, Jørgensen T, Jukema JW, Juonala M, Kanoni S, Karaleftheri M, Khaw KT, Kinnunen L, Kittner SJ, Koenig W, Kolcic I, Kovacs P, Krarup NT, Kratzer W, Krüger J, Kuh D, Kumari M, Kyriakou T, Langenberg C, Lannfelt L, Lanzani C, Lotay V, Launer LJ, Leander K, Lindström J, Linneberg A, Liu YP, Lobbens S, Luben R, Lyssenko V, Männistö S, Magnusson PK, McArdle WL, Menni C, Merger S, Milani L, Montgomery GW, Morris AP, Narisu N, Nelis M, Ong KK, Palotie A, Pérusse L, Pichler I, Pilia MG, Pouta A, Rheinberger M, Ribel-Madsen R, Richards M, Rice KM, Rice TK, Rivolta C, Salomaa V, Sanders AR, Sarzynski MA, Scholtens S, Scott RA, Scott WR, Sebert S, Sengupta S, Sennblad B, Seufferlein T, Silveira A, Slagboom PE, Smit JH, Sparsø TH, Stirrups K, Stolk RP, Stringham HM, Swertz MA, Swift AJ, Syvänen AC, Tan ST, Thorand B, Tönjes A, Tremblay A, Tsafantakis E, van der Most PJ, Völker U, Vohl MC, Vonk JM, Waldenberger M, Walker RW, Wennauer R, Widén E, Willemsen G, Wilsgaard T, Wright AF, Zillikens MC, van Dijk SC, van Schoor NM, Asselbergs FW, de Bakker PI, Beckmann JS, Beilby J, Bennett DA, Bergman RN, Bergmann S, Böger CA, Boehm BO, Boerwinkle E, Boomsma DI, Bornstein SR, Bottinger EP, Bouchard C, Chambers JC, Chanock SJ, Chasman DI, Cucca F, Cusi D, Dedoussis G, Erdmann J, Eriksson JG, Evans DA, de Faire U, Farrall M, Ferrucci L, Ford I, Franke L, Franks PW, Froguel P, Gansevoort RT, Gieger C, Grönberg H, Gudnason V, Gyllensten U, Hall P, Hamsten A, van der Harst P, Hayward C, Heliövaara M, Hengstenberg C, Hicks AA, Hingorani A, Hofman A, Hu F, Huikuri HV, Hveem K, James AL, Jordan JM, Jula A, Kähönen M, Kajantie E, Kathiresan S, Kiemeney LA, Kivimaki M, Knekt PB, Koistinen HA, Kooner JS, Koskinen S, Kuusisto J, Maerz W, Martin NG, Laakso M, Lakka TA, Lehtimäki T, Lettre G, Levinson DF, Lind L, Lokki ML, Mäntyselkä P, Melbye M, Metspalu A, Mitchell BD, Moll FL, Murray JC, Musk AW, Nieminen MS, Njølstad I, Ohlsson C, Oldehinkel AJ, Oostra BA, Palmer LJ, Pankow JS, Pasterkamp G, Pedersen NL, Pedersen O, Penninx BW, Perola M, Peters A, Polašek O, Pramstaller PP, Psaty BM, Qi L, Quertermous T, Raitakari OT, Rankinen T, Rauramaa R, Ridker PM, Rioux JD, Rivadeneira F, Rotter JI, Rudan I, den Ruijter HM, Saltevo J, Sattar N, Schunkert H, Schwarz PE, Shuldiner AR, Sinisalo J, Snieder H, Sørensen TI, Spector TD, Staessen JA, Stefania B, Thorsteinsdottir U, Stumvoll M, Tardif JC, Tremoli E, Tuomilehto J, Uitterlinden AG, Uusitupa M, Verbeek AL, Vermeulen SH, Viikari JS, Vitart V, Völzke H, Vollenweider P, Waeber G, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Zeggini E, Chakravarti A, Clegg DJ, Cupples LA, Gordon-Larsen P, Jaquish CE, Rao DC, Abecasis GR, Assimes TL, Barroso I, Berndt SI, Boehnke M, Deloukas P, Fox CS, Groop LC, Hunter DJ, Ingelsson E, Kaplan RC, McCarthy MI, Mohlke KL, O'Connell JR, Schlessinger D, Strachan DP, Stefansson K, van Duijn CM, Hirschhorn JN, Lindgren CM, Heid IM, North KE, Borecki IB, Kutalik Z, and Loos RJ

Subjects
Adult, Age Factors, Aged, Chromosome Mapping, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Sex Characteristics, Waist-Hip Ratio, White People, Body Mass Index, Body Size genetics, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Published
2015
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14. Replication of 13q31.1 association in nonsyndromic cleft lip with cleft palate in Europeans.

Author

Jia Z, Leslie EJ, Cooper ME, Butali A, Standley J, Rigdon J, Suzuki S, Gongorjav A, Shonkhuuz TE, Natsume N, Shi B, Marazita ML, and Murray JC

Subjects
Asian People genetics, Cleft Lip physiopathology, Cleft Palate physiopathology, Female, Genome-Wide Association Study, Humans, Male, Pedigree, Polymorphism, Single Nucleotide, Risk, White People genetics, Chromosomes, Human, Pair 13 genetics, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease
Abstract

Genome wide association (GWA) studies have successfully identified at least a dozen loci associated with orofacial clefts. However, these signals may be unique to specific populations and require replication to validate and extend findings as a prelude to etiologic SNP discovery. We attempted to replicate the findings of a recent meta-analysis of orofacial cleft GWA studies using four different ancestral populations. We studied 946 pedigrees (3,436 persons) of European (US white and Danish) and Asian (Japanese and Mongolian) origin. We genotyped six SNPs that represented the most significant P-value associations identified in published studies: rs742071 (1p36), rs7590268 (2p21), rs7632427 (3p11.1), rs12543318 (8q21.3), rs8001641 (13q31.1), and rs7179658 (15q22.2). We directly sequenced three non-coding conserved regions 200 kb downstream of SPRY2 in 713 cases, 438 controls, and 485 trios from the US, Mongolia, and the Philippines. We found rs8001641 to be significantly associated with nonsyndromic cleft lip with cleft palate (NSCLP) in Europeans (P-value = 4 × 10(-5), ORtransmission = 1.86 with 95% confidence interval: 1.38-2.52). We also found several novel sequence variants in the conserved regions in Asian and European samples, which may help to localize common variants contributing directly to the risk for NSCLP. This study confirms the prior association between rs8001641 and NSCLP in European populations., (© 2015 Wiley Periodicals, Inc.)

Published
2015
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15. Antioxidant response genes sequence variants and BPD susceptibility in VLBW infants.

Author

Sampath V, Garland JS, Helbling D, Dimmock D, Mulrooney NP, Simpson PM, Murray JC, and Dagle JM

Subjects
Enzyme Induction genetics, Genotype, Humans, Infant, Newborn, Models, Genetic, NF-E2-Related Factor 2 metabolism, Antioxidant Response Elements genetics, Bronchopulmonary Dysplasia genetics, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Infant, Very Low Birth Weight
Abstract

Background: Lung injury resulting from oxidative stress contributes to bronchopulmonary dysplasia (BPD) pathogenesis. Nuclear factor erythroid-2 related factor-2 (NFE2L2) regulates cytoprotective responses to oxidative stress by inducing enzymes containing antioxidant response elements (ARE). We hypothesized that ARE genetic variants will modulate susceptibility or severity of BPD in very-low-birth-weight (VLBW) infants., Methods: Blood samples obtained from VLBW infants were used for genotyping variants in the SOD2, NFE2L2, GCLC, GSTP1, HMOX1, and NQO1 genes. SNPs were genotyped utilizing TaqMan probes (Applied Biosystems (ABI), Grand Island, NY), and data were analyzed using the ABI HT7900. Genetic dominance and recessive models were tested to determine associations between SNPs and BPD., Results: In our cohort (n = 659), 284 infants had BPD; 135 of whom developed severe BPD. Presence of the hypomorphic NQO1 SNP (rs1800566) in a homozygous state was associated with increased BPD, while presence of the NFE2L2 SNP (rs6721961) was associated with decreased severe BPD in the entire cohort and in Caucasian infants. In regression models that adjusted for epidemiological confounders, the NQO1 and the NFE2L2 SNPs were associated with BPD and severe BPD, respectively., Conclusion: Genetic variants in NFE2L2-ARE axis may contribute to the variance in liability to BPD observed in preterm infants. These results require confirmation in independent cohorts.

Published
2015
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16. Integrated genomic analyses in bronchopulmonary dysplasia.

Author

Ambalavanan N, Cotten CM, Page GP, Carlo WA, Murray JC, Bhattacharya S, Mariani TJ, Cuna AC, Faye-Petersen OM, Kelly D, and Higgins RD

Subjects
Animals, Bronchopulmonary Dysplasia epidemiology, Genome-Wide Association Study, Genotype, Gestational Age, Humans, Incidence, Infant, Infant, Extremely Low Birth Weight, Infant, Newborn, Infant, Premature, Mice, Survival Rate trends, United States epidemiology, Bronchopulmonary Dysplasia genetics, DNA genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
Abstract

Objective: To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors., Study Design: A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models., Results: Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) <0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD., Conclusions: Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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17. Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate.

Author

Wu T, Schwender H, Ruczinski I, Murray JC, Marazita ML, Munger RG, Hetmanski JB, Parker MM, Wang P, Murray T, Taub M, Li S, Redett RJ, Fallin MD, Liang KY, Wu-Chou YH, Chong SS, Yeow V, Ye X, Wang H, Huang S, Jabs EW, Shi B, Wilcox AJ, Jee SH, Scott AF, and Beaty TH

Subjects
Asian People genetics, Female, Humans, Logistic Models, Male, Polymorphism, Single Nucleotide genetics, Risk Factors, Chromosomes, Human, Pair 4 genetics, Cleft Palate genetics, Gene-Environment Interaction, Genetic Predisposition to Disease, Glucose Transport Proteins, Facilitative genetics, Microfilament Proteins genetics, Tobacco Smoke Pollution adverse effects
Abstract

Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10(-6)

Published
2014
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18. Oral cleft recurrence risk and subsequent maternal fertility preferences and behavior in Brazil.

Author

Wehby GL, Nyarko KA, and Murray JC

Subjects
Adult, Brazil, Child, Cleft Lip genetics, Cleft Lip pathology, Cleft Palate genetics, Cleft Palate pathology, Contraception Behavior psychology, Counseling, Educational Status, Family Planning Services, Female, Humans, Inheritance Patterns, Male, Maternal Age, Patient Education as Topic, Regression Analysis, Risk, Cleft Lip psychology, Cleft Palate psychology, Fertility, Genetic Predisposition to Disease, Mothers psychology
Abstract

Background: Oral clefts are among the most common birth defects with numerous impacts on affected individuals and families. However, little is known about how being at a greater risk of having an affected child affects subsequent maternal fertility decisions. We investigated differences in fertility preferences and behavior between mothers who are themselves affected with cleft lip with/without cleft palate but have had no affected children and unaffected mothers of an affected child. We also compared these outcomes between unaffected mothers of a first versus another affected child., Methods: The sample included 1475 Brazilian women interviewed between 2004 and 2009. The outcomes were wanting more children, contraceptive use and type, and maternal age at first child. Comparisons between the various maternal groups were performed using regression analysis adjusting for conceptually relevant demographic, socioeconomic, and geographic factors., Results: Affected mothers of unaffected children were less likely to use contraceptives than unaffected mothers of affected children by 31% (95% confidence interval, 1-53%). Among unaffected mothers, those who had a first affected child were 67% (95% confidence interval, 15-144%) more likely to use contraceptives., Conclusion: The results suggest that having an affected child represents a stronger signal of recurrence risk to the mother than her own cleft status, and that cleft status of the first child is especially important in influencing subsequent maternal fertility decisions in affected families. These findings highlight the importance of adequate counseling of at-risk women about recurrence risks and available care resources and policies that improve access to quality cleft care., (Copyright © 2013 Wiley Periodicals, Inc.)

Published
2014
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20. Genetic associations of surfactant protein D and angiotensin-converting enzyme with lung disease in preterm neonates.

Author

Ryckman KK, Dagle JM, Kelsey K, Momany AM, and Murray JC

Subjects
Alleles, Bronchopulmonary Dysplasia diagnosis, Bronchopulmonary Dysplasia epidemiology, Cohort Studies, DNA analysis, DNA genetics, Female, Gene Expression Regulation, Developmental, Genetic Testing, Gestational Age, Humans, Incidence, Infant, Newborn, Intensive Care Units, Neonatal, Male, Neonatal Screening, Pregnancy, Prognosis, Renin-Angiotensin System genetics, Renin-Angiotensin System physiology, Respiratory Distress Syndrome, Newborn diagnosis, Respiratory Distress Syndrome, Newborn epidemiology, Respiratory Distress Syndrome, Newborn genetics, Retrospective Studies, Risk Assessment, Sex Distribution, Survival Rate, Bronchopulmonary Dysplasia genetics, Genetic Predisposition to Disease, Infant, Premature, Peptidyl-Dipeptidase A genetics, Polymorphism, Single Nucleotide, Pulmonary Surfactant-Associated Protein D genetics
Abstract

Objective: To replicate genetic associations with respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in genes related to surfactant deficiency, inflammation and infection, and the renin-angiotensin system., Study Design: We examined eight candidate genes for associations with RDS and BPD in 433 preterm birth (PTB-<37 weeks) infants (251 with RDS and 134 with BPD). Both case-control and family-based analyses were performed in preterm (<37 weeks) and very preterm birth (VPTB-<32 weeks) infants., Result: We replicated a previous finding that rs1923537, a marker downstream of surfactant protein D (SFTPD) is associated with RDS in VPTB infants in that the T allele was overtransmitted from parents to offspring with RDS (P=8.4 × 10(-3)). We also observed the A allele of rs4351 in the angiotensin-converting enzyme (ACE) gene was overtransmitted from parents to VPTB offspring with BPD (P=9.8 × 10(-3))., Conclusion: These results give further insight into the genetic risk factors for complex neonatal respiratory diseases and provide more evidence of the importance of SFTPD and ACE in the etiology of RDS and BPD, respectively.

Published
2012
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21. Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis.

Author

Feenstra B, Geller F, Krogh C, Hollegaard MV, Gørtz S, Boyd HA, Murray JC, Hougaard DM, and Melbye M

Subjects
Denmark, Genome-Wide Association Study, Homeobox Protein Nkx-2.5, Humans, Infant, Odds Ratio, Polymorphism, Single Nucleotide genetics, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 5 genetics, Genetic Predisposition to Disease genetics, Homeodomain Proteins genetics, Pyloric Stenosis, Hypertrophic genetics, RNA-Binding Proteins genetics, Transcription Factors genetics
Abstract

Infantile hypertrophic pyloric stenosis (IHPS) is a severe condition characterized by hypertrophy of the pyloric sphincter muscle. We conducted a genome-wide association study (GWAS) on 1,001 surgery-confirmed cases and 2,401 controls from Denmark. The six most strongly associated loci were tested in a replication set of 796 cases and 876 controls. Three SNPs reached genome-wide significance. One of these SNPs, rs11712066 (odds ratio (OR) = 1.61; P = 1.5 × 10(-17)) at 3p25.1, is located 150 kb upstream of MBNL1, which encodes a factor that regulates splicing transitions occurring shortly after birth. The second SNP, rs573872 (OR = 1.41; P = 4.3 × 10(-12)), maps to an intergenic region at 3p25.2 approximately 1.3 Mb downstream of MBNL1. The third SNP, rs29784 (OR = 1.42; P = 1.5 × 10(-15)) at 5q35.2, is 64 kb downstream of NKX2-5, which is involved in development of cardiac muscle tissue and embryonic gut development.

Published
2012
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22. Genome-wide association scan for childhood caries implicates novel genes.

Author

Shaffer JR, Wang X, Feingold E, Lee M, Begum F, Weeks DE, Cuenco KT, Barmada MM, Wendell SK, Crosslin DR, Laurie CC, Doheny KF, Pugh EW, Zhang Q, Feenstra B, Geller F, Boyd HA, Zhang H, Melbye M, Murray JC, Weyant RJ, Crout R, McNeil DW, Levy SM, Slayton RL, Willing MC, Broffitt B, Vieira AR, and Marazita ML

Subjects
Child, Child, Preschool, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 17, Genetic Loci, HapMap Project, Humans, Polymorphism, Single Nucleotide, United States, Dental Caries genetics, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Dental caries is the most common chronic disease in children and a major public health concern due to its increasing incidence, serious health and social co-morbidities, and socio-demographic disparities in disease burden. We performed the first genome-wide association scan for dental caries to identify associated genetic loci and nominate candidate genes affecting tooth decay in 1305 US children ages 3-12 yrs. Affection status was defined as 1 or more primary teeth with evidence of decay based on intra-oral examination. No associations met strict criteria for genome-wide significance (p < 10E-7); however, several loci (ACTN2, MTR, and EDARADD, MPPED2, and LPO) with plausible biological roles in dental caries exhibited suggestive evidence for association. Analyses stratified by home fluoride level yielded additional suggestive loci, including TFIP11 in the low-fluoride group, and EPHA7 and ZMPSTE24 in the sufficient-fluoride group. Suggestive loci were tested but not significantly replicated in an independent sample (N = 1695, ages 2-7 yrs) after adjustment for multiple comparisons. This study reinforces the complexity of dental caries, suggesting that numerous loci, mostly having small effects, are involved in cariogenesis. Verification/replication of suggestive loci may highlight biological mechanisms and/or pathways leading to a fuller understanding of the genetic risks for dental caries.

Published
2011
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23. Risk of oral clefts in twins.

Author

Grosen D, Bille C, Petersen I, Skytthe A, Hjelmborg Jv, Pedersen JK, Murray JC, and Christensen K

Subjects
Cleft Lip epidemiology, Cleft Lip surgery, Databases, Factual, Denmark epidemiology, Diseases in Twins epidemiology, Follow-Up Studies, Humans, Infant, Newborn, Male, Prevalence, Reference Values, Registries, Risk Assessment, Sex Distribution, Twins, Dizygotic, Twins, Monozygotic, Cleft Lip genetics, Diseases in Twins genetics, Genetic Predisposition to Disease epidemiology
Abstract

Background: Small studies have indicated that twinning increases the risk of oral cleft., Methods: We used data from a Danish national population-based cohort study to investigate whether twinning was associated with isolated oral cleft, and to estimate the twin probandwise concordance rate and heritability. Twins (207 affected/130,710) and singletons (7766 affected/4,798,526) born from 1936 through 2004 in Denmark were ascertained by linkage among the Danish Facial Cleft Database, the Danish Twin Registry, and the Civil Registration System. We computed oral cleft prevalence and prevalence proportion ratio for twins versus singletons, stratified for 3 subphenotypes. Probandwise concordance rates and heritability for twins were estimated for 2 phenotypes--cleft lip with or without cleft palate (CL/P) and cleft palate (CP)., Results: The prevalence of oral cleft was 15.8 per 10,000 twins and 16.6 per 10,000 singletons (prevalence proportion ratio = 0.95; 95% confidence interval = 0.83-1.1). This prevalence was similar for monozygotic and dizygotic twins. The probandwise concordance rate was higher for CL/P for monozygotic twins than for dizygotic twins (50% vs. 8%, respectively). A similar contrast was present for CP. Recurrence risk for both types of clefts was greater in dizygotic twins than in non-twin siblings. Heritability estimates were above 90% for both CL/P and CP., Conclusions: No excess risk of oral cleft could be demonstrated for twins compared with singletons. The concordance rates and heritability estimates for both types of clefts show a strong genetic component.

Published
2011
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24. Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis.

Author

Haataja R, Karjalainen MK, Luukkonen A, Teramo K, Puttonen H, Ojaniemi M, Varilo T, Chaudhari BP, Plunkett J, Murray JC, McCarroll SA, Peltonen L, Muglia LJ, Palotie A, and Hallman M

Subjects
Case-Control Studies, Female, Finland, Genetic Linkage, Genome-Wide Association Study, Haplotypes genetics, Humans, Male, Polymorphism, Single Nucleotide genetics, Pregnancy, Genetic Predisposition to Disease, Premature Birth genetics, Receptor, IGF Type 1 genetics
Abstract

Preterm birth is the major cause of neonatal death and serious morbidity. Most preterm births are due to spontaneous onset of labor without a known cause or effective prevention. Both maternal and fetal genomes influence the predisposition to spontaneous preterm birth (SPTB), but the susceptibility loci remain to be defined. We utilized a combination of unique population structures, family-based linkage analysis, and subsequent case-control association to identify a susceptibility haplotype for SPTB. Clinically well-characterized SPTB families from northern Finland, a subisolate founded by a relatively small founder population that has subsequently experienced a number of bottlenecks, were selected for the initial discovery sample. Genome-wide linkage analysis using a high-density single-nucleotide polymorphism (SNP) array in seven large northern Finnish non-consanginous families identified a locus on 15q26.3 (HLOD 4.68). This region contains the IGF1R gene, which encodes the type 1 insulin-like growth factor receptor IGF-1R. Haplotype segregation analysis revealed that a 55 kb 12-SNP core segment within the IGF1R gene was shared identical-by-state (IBS) in five families. A follow-up case-control study in an independent sample representing the more general Finnish population showed an association of a 6-SNP IGF1R haplotype with SPTB in the fetuses, providing further evidence for IGF1R as a SPTB predisposition gene (frequency in cases versus controls 0.11 versus 0.05, P = 0.001, odds ratio 2.3). This study demonstrates the identification of a predisposing, low-frequency haplotype in a multifactorial trait using a well-characterized population and a combination of family and case-control designs. Our findings support the identification of the novel susceptibility gene IGF1R for predisposition by the fetal genome to being born preterm., Competing Interests: The authors have declared that no competing interests exist.

Published
2011
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25. Fetal genetic risk of isolated cleft lip only versus isolated cleft lip and palate: a subphenotype analysis using two population-based studies of orofacial clefts in Scandinavia.

Author

Jugessur A, Shi M, Gjessing HK, Lie RT, Wilcox AJ, Weinberg CR, Christensen K, Boyles AL, Daack-Hirsch S, Nguyen TT, Christiansen L, Lidral AC, and Murray JC

Subjects
Cleft Lip epidemiology, Cleft Palate epidemiology, Connexin 43 genetics, Female, Fibroblast Growth Factors genetics, Humans, Interferon Regulatory Factors genetics, Male, Phenotype, Polymorphism, Single Nucleotide, Scandinavian and Nordic Countries epidemiology, Vinculin genetics, Cleft Lip genetics, Cleft Palate genetics, Genetic Association Studies, Genetic Predisposition to Disease
Published
2011
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26. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4.

Author

Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, Redett RA, Raymond G, Schwender H, Jin SC, Cooper ME, Dunnwald M, Mansilla MA, Leslie E, Bullard S, Lidral AC, Moreno LM, Menezes R, Vieira AR, Petrin A, Wilcox AJ, Lie RT, Jabs EW, Wu-Chou YH, Chen PK, Wang H, Ye X, Huang S, Yeow V, Chong SS, Jee SH, Shi B, Christensen K, Melbye M, Doheny KF, Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody L, Pangilinan F, Mills JL, Molloy AM, Kirke PN, Scott JM, Arcos-Burgos M, and Scott AF

Subjects
Animals, Asian People genetics, Female, Genome-Wide Association Study, Genotype, Humans, Mice, White People genetics, ATP-Binding Cassette Transporters genetics, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease, MafB Transcription Factor genetics, Polymorphism, Single Nucleotide
Abstract

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

Published
2010
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27. Determination of genetic predisposition to patent ductus arteriosus in preterm infants.

Author

Dagle JM, Lepp NT, Cooper ME, Schaa KL, Kelsey KJ, Orr KL, Caprau D, Zimmerman CR, Steffen KM, Johnson KJ, Marazita ML, and Murray JC

Subjects
Cholesterol Ester Transfer Proteins genetics, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 Enzyme System genetics, Gestational Age, Haplotypes, Humans, Infant, Newborn, Infant, Premature, Intramolecular Oxidoreductases genetics, Lipase genetics, Receptor, Angiotensin, Type 1 genetics, Receptors, Corticotropin-Releasing Hormone genetics, TNF Receptor-Associated Factor 1 genetics, Transcription Factor AP-2 genetics, Ductus Arteriosus, Patent genetics, Genetic Predisposition to Disease epidemiology, Infant, Premature, Diseases genetics, Polymorphism, Single Nucleotide
Abstract

Objective: Patent ductus arteriosus is a common morbidity associated with preterm birth. The incidence of patent ductus arteriosus increases with decreasing gestational age to approximately 70% in infants born at 25 weeks' gestation. Our major goal was to determine if genetic risk factors play a role in patent ductus arteriosus seen in preterm infants., Methodology: We investigated whether single-nucleotide polymorphisms in genes that regulate smooth muscle contraction, xenobiotic detoxification, inflammation, and other processes are markers for persistent patency of ductus arteriosus. Initially, 377 single-nucleotide polymorphisms from 130 genes of interest were evaluated in DNA samples collected from 204 infants with a gestational age of <32 weeks. A family-based association test was performed on genotyping data to evaluate overtransmission of alleles., Results: P values of <.01 were detected for genetic variations found in 7 genes. This prompted additional analysis with an additional set of 162 infants, focusing on the 7 markers with initial P values of <.01, and 1 genetic variant in the angiotensin II type I receptor previously shown to be related to patent ductus arteriosus. Of the initial positive signals, single-nucleotide polymorphisms in the transcription factor AP-2 beta and tumor necrosis factor receptor-associated factor 1 genes remained significant. Additional haplotype analysis revealed genetic variations in prostacyclin synthase to be associated with patent ductus arteriosus. An angiotensin II type I receptor polymorphism previously reported to be associated with patent ductus arteriosus after prophylactic indomethacin administration was not associated with the presence of a patent ductus arteriosus in our population., Conclusions: Overall, our data support a role for genetic variations in transcription factor AP-2 beta, tumor necrosis factor receptor-associated factor 1, and prostacyclin synthase in the persistent patency of the ductus arteriosus seen in preterm infants.

Published
2009
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28. Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip.

Author

Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubini M, Domann FE, Govil M, Christensen K, Bille C, Melbye M, Jugessur A, Lie RT, Wilcox AJ, Fitzpatrick DR, Green ED, Mossey PA, Little J, Steegers-Theunissen RP, Pennacchio LA, Schutte BC, and Murray JC

Subjects
Alleles, Animals, Base Sequence, Binding Sites, Case-Control Studies, Conserved Sequence, Haplotypes, Humans, Mice, Mice, Transgenic, Molecular Sequence Data, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide genetics, Protein Binding, Cleft Lip genetics, Enhancer Elements, Genetic genetics, Genetic Predisposition to Disease, Interferon Regulatory Factors genetics, Transcription Factor AP-2 metabolism
Abstract

Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 x 10(-11)) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2alpha and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2alpha in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.

Published
2008
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29. What genome-wide association studies can do for medicine.

Author

Christensen K and Murray JC

Subjects
Genetic Diseases, Inborn genetics, Genetic Variation, Haplotypes, Humans, Linkage Disequilibrium, Risk Factors, Sequence Analysis, DNA, Genetic Predisposition to Disease genetics, Genome, Human, Mutation, Polymorphism, Single Nucleotide
Published
2007
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30. Medical sequencing of candidate genes for nonsyndromic cleft lip and palate.

Author

Vieira AR, Avila JR, Daack-Hirsch S, Dragan E, Félix TM, Rahimov F, Harrington J, Schultz RR, Watanabe Y, Johnson M, Fang J, O'Brien SE, Orioli IM, Castilla EE, Fitzpatrick DR, Jiang R, Marazita ML, and Murray JC

Subjects
Databases, Genetic, Family Health, Female, Genetic Linkage, Humans, Linkage Disequilibrium, MSX1 Transcription Factor genetics, Male, Pedigree, Point Mutation, Polymorphism, Genetic, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease, Sequence Analysis, DNA
Abstract

Nonsyndromic or isolated cleft lip with or without cleft palate (CL/P) occurs in wide geographic distribution with an average birth prevalence of 1/700. We used direct sequencing as an approach to study candidate genes for CL/P. We report here the results of sequencing on 20 candidate genes for clefts in 184 cases with CL/P selected with an emphasis on severity and positive family history. Genes were selected based on expression patterns, animal models, and/or role in known human clefting syndromes. For seven genes with identified coding mutations that are potentially etiologic, we performed linkage disequilibrium studies as well in 501 family triads (affected child/mother/father). The recently reported MSX1 P147Q mutation was also studied in an additional 1,098 cleft cases. Selected missense mutations were screened in 1,064 controls from unrelated individuals on the Centre d'Etude du Polymorphisme Humain (CEPH) diversity cell line panel. Our aggregate data suggest that point mutations in these candidate genes are likely to contribute to 6% of isolated clefts, particularly those with more severe phenotypes (bilateral cleft of the lip with cleft palate). Additional cases, possibly due to microdeletions or isodisomy, were also detected and may contribute to clefts as well. Sequence analysis alone suggests that point mutations in FOXE1, GLI2, JAG2, LHX8, MSX1, MSX2, SATB2, SKI, SPRY2, and TBX10 may be rare causes of isolated cleft lip with or without cleft palate, and the linkage disequilibrium data support a larger, as yet unspecified, role for variants in or near MSX2, JAG2, and SKI. This study also illustrates the need to test large numbers of controls to distinguish rare polymorphic variants and prioritize functional studies for rare point mutations., Competing Interests: Competing interests. The authors have declared that no competing interests exist.

Published
2005
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32. Genetic approaches to identify disease genes for birth defects with cleft lip/palate as a model.

Author

Lidral AC and Murray JC

Subjects
Humans, Pedigree, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Teratogens toxicity, Chromosome Aberrations, Chromosome Mapping, Cleft Lip genetics, Cleft Palate genetics, Congenital Abnormalities genetics, Genetic Predisposition to Disease
Abstract

Background: Understanding the etiology of birth defects is an important step toward developing improved treatment and preventive strategies. Most birth defects have an underlying genetic basis, ranging from single genes playing dominant or recessive roles in Mendelian disorders to a mixture of contributions from multiple genes and environmental triggers in complex traits. The purpose of this article is to provide an overview of genetic approaches to identifying disease genes for genetically complex birth defects., Methods: A review of the literature describing successes and limitations for identifying disease genes for complex traits was conducted., Results: Cleft lip and cleft palate are common congenital anomalies with significant medical, psychological, social, and economic ramifications. The Online Mendelian Inheritance in Man catalog (OMIM; http://www3.ncbi.nlm.nih.gov/Omim) lists more than 400 single-gene causes of clefts of the lip and/or palate. Genetic causes of clefting also include chromosomal rearrangements, genetic susceptibility to teratogenic exposures, and complex genetic contributions of multiple genes., Conclusions: Genetic causes of birth defects can be identified using an increasingly powerful combination of careful sample collection, molecular analytic methods, and statistical evaluations. We will describe a range of approaches to search for genetic factors of birth defects and use our own work with cleft lip and palate as a model.

Published
2004
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33. Targeted scan of fifteen regions for nonsyndromic cleft lip and palate in Filipino families.

Author

Schultz RE, Cooper ME, Daack-Hirsch S, Shi M, Nepomucena B, Graf KA, O'Brien EK, O'Brien SE, Marazita ML, and Murray JC

Subjects
Chromosome Mapping methods, Cleft Lip pathology, Cleft Palate pathology, Family Health, Female, Genotype, Humans, Linkage Disequilibrium, Lod Score, Male, Microsatellite Repeats, Pedigree, Philippines, Cleft Lip genetics, Cleft Palate genetics, Genetic Predisposition to Disease genetics
Abstract

Cleft lip with or without cleft palate (CL/P) is a congenital anomaly with variable birth prevalence based on geographic origins, with the highest rates commonly found in Asian populations. About 70% of cases are nonsyndromic (NS), in which the affected individual has no other abnormalities. NS CL/P is a complex disorder with genetic and environmental effects and no specific genetic loci yet confirmed. Fifteen candidate regions were examined for linkage to NS CL/P. Regions were chosen based on previous suggestive linkage and/or association in human families, or suggestive animal model data. Polymorphic markers in these regions were genotyped for analysis on 36 Filipino families comprised of 126 affected and 218 unaffected individuals. An additional 70 families with 149 affecteds were used for replication of suggestive results. Parametric (LOD score) and nonparametric (SIMIBD) linkage analyses were performed as well as transmission disequilibrium test (TDT) analysis. Five markers yielded suggestive results from the 36 families. The parametric LOD scores for the MSX1-CA and D4S1629 were >1.0 and the SIMIBD P values for D6S1029 and RFC1 are suggestive (<0.06), while the SIMIBD P value of 0.01 for TGFA was significant. Since the Msx1 mouse knockout has cleft palate and MSX1 mutations have been found in rare cases of syndromic CL/P, this locus is especially plausible for linkage. Previous studies have also found linkage of NS CL/P to 4q31 and 6p23. These regions contain several candidate genes, including AP2 at 6p23 and FGF2, BMPR1B, and MADH1 at 4q31. TGFA has both linkage and linkage disequilibrium data supporting it as a candidate gene for NS CL/P. While no region was definitively confirmed for linkage to NS CL/P, the data do support further investigation using larger sample sizes and candidate gene studies at 2p13.2, 4p16.2, 4q31, 6p23, and 16q22-24., (Copyright 2003 Wiley-Liss, Inc.)

Published
2004
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34. Association between the tumor necrosis factor locus and the clinical outcome of Leishmania chagasi infection.

Author

Karplus TM, Jeronimo SM, Chang H, Helms BK, Burns TL, Murray JC, Mitchell AA, Pugh EW, Braz RF, Bezerra FL, and Wilson ME

Subjects
Adult, Alleles, Animals, Case-Control Studies, Child, Child, Preschool, Family, Female, Gene Frequency, Humans, Hypersensitivity, Delayed genetics, Hypersensitivity, Delayed parasitology, Leishmania infantum pathogenicity, Leishmaniasis, Visceral genetics, Leishmaniasis, Visceral parasitology, Lymphotoxin-alpha, Male, Microsatellite Repeats genetics, Polymorphism, Restriction Fragment Length, Tumor Necrosis Factor-alpha metabolism, Genetic Predisposition to Disease, Hypersensitivity, Delayed physiopathology, Leishmania infantum immunology, Leishmaniasis, Visceral physiopathology, Tumor Necrosis Factor-alpha genetics
Abstract

A periurban outbreak of visceral leishmaniasis (VL) caused by the protozoan Leishmania chagasi is ongoing outside Natal, northeast Brazil. Manifestations range from asymptomatic infection to disseminated visceral disease. Literature reports suggest that both genetic and environmental factors influence the outcome of infection. Due to the association of the tumor necrosis factor (TNF) locus with other infectious diseases, we examined whether polymorphic alleles at this locus are associated with the outcome of L. chagasi infection. Neighborhoods with ongoing transmission were identified through patients admitted to local hospitals. Altogether, 1,024 individuals from 183 families were classified with the following disease phenotypes: (i) symptomatic VL, (ii) asymptomatic infection (positive delayed-type hypersensitivity [DTH+]), or (iii) no evidence of infection (DTH-). Genotypes were determined at a microsatellite marker (MSM) upstream of the TNFB gene encoding TNF-beta and at a restriction fragment length polymorphism (RFLP) at position -307 in the promoter of the TNFA gene encoding TNF-alpha. Analyses showed that the distribution of TNFA RFLP alleles (TNF1 and TNF2) and the TNF MSM alleles (TNFa1 to TNFa15) differed between individuals with VL and those with DTH+ phenotypes. TNF1 was transmitted more frequently than expected from heterozygous parents to DTH+ offspring (P = 0.0006), and haplotypes containing TNF2 were associated with symptomatic VL (P = 0.0265, transmission disequilibrium test). Resting serum TNF-alpha levels were higher in TNF1/2 heterozygotes than in TNF1/1 homozygotes (P < 0.05). These data led us to hypothesize that an individual's genotype at the TNF locus may be associated with whether he or she develops asymptomatic or symptomatic disease after L. chagasi infection. The results preliminarily suggest that this may be the case, and follow-up with larger populations is needed for verification.

Published
2002
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35. Genetic loci for pathological myopia are not associated with juvenile myopia.

Author

Mutti DO, Semina E, Marazita M, Cooper M, Murray JC, and Zadnik K

Subjects
Child, Chromosome Mapping, Humans, Lod Score, Microsatellite Repeats, Models, Genetic, Myopia pathology, Genetic Predisposition to Disease genetics, Myopia genetics
Abstract

The purpose of this study was to evaluate chromosomal regions previously linked to pathological myopia for linkage to juvenile myopia in a sample of myopic children and their families. Of 125 families with a myopic child participating in the Orinda longitudinal study of myopia, 53 submitted 221 buccal swab samples for genetic analysis. Myopia in proband children was defined as -0.75 D or more myopia in both meridians on cycloplegic autorefraction (1% tropicamide). Affected status in parents and siblings was obtained by survey. DNA was extracted from buccal mucosal cells, amplified by polymerase chain reaction (PCR), and then analyzed with seven markers for chromosome 12 and five markers for chromosome 18 in the regions previously associated with pathological myopia. LOD scores were not significant for any marker tested. The largest positive LOD score was 0.15 for GATA30F04. Model-free methods using a SimIBD approach suggested a possible linkage at one marker, GATA6H09 (P = 0.003), but these results were not supported by transmission disequilibrium test (TDT) analysis. The statistical power to detect LOD scores of > or =1.0, assuming homogeneity, was estimated at 93.2%. We found no confirmatory evidence of linkage between juvenile myopia and regions of chromosomes 12 and 18 previously associated with pathological myopia., (Copyright 2002 Wiley-Liss, Inc.)

Published
2002
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36. Genetic susceptibility to preeclampsia: roles of cytosineto-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine beta-synthase, and factor V Leiden mutation.

Author

Kim YJ, Williamson RA, Murray JC, Andrews J, Pietscher JJ, Peraud PJ, and Merrill DC

Subjects
Amino Acid Substitution, Female, Gene Frequency, Heterozygote, Homozygote, Humans, Methylenetetrahydrofolate Reductase (NADPH2), Pregnancy, Cystathionine beta-Synthase genetics, DNA Transposable Elements, Factor V genetics, Genetic Predisposition to Disease, Mutation, Missense physiology, Oxidoreductases Acting on CH-NH Group Donors genetics, Pre-Eclampsia genetics
Abstract

Objective: The purpose of this study was to evaluate the association between preeclampsia and 3 relatively common mutations that are important in the development of vascular disease and thrombosis; these are similar to conditions observed in pregnancies complicated by preeclampsia., Study Design: Deoxyribonucleic acid was extracted from whole blood or cheek swabs of 281 patients with preeclampsia and 360 control subjects (all white). Control subjects consisted of women who had undergone at least 2 term pregnancies unaffected by preeclampsia. Mutation frequencies among patients with preeclampsia and control subjects were compared by standard chi2 analysis, with P <.05 considered significant., Results: Thirty-three of 281 women with preeclampsia (11.7%) and 22 of 193 women with severe preeclampsia (11.4%) were homozygous for cytosine-to-thymine substitution at nucleotide 677 in the gene for methyltetrahydrofolate reductase (MTHFR), versus 41 of 360 control subjects (11.4%; difference not significant). Forty of 258 women with preeclampsia (15.5%) and 22 of 175 women with severe preeclampsia (12.6%) were heterozygous for the insertion of 68 bases at position 844 in the gene for cystathionine beta-synthase (CBS), versus 58 of 332 control subjects (17.5%). Fifteen of 250 women with preeclampsia (6.0%) and 11 of 169 with severe preeclampsia (6.5%) were heterozygous for the Leiden mutation (glycine-to-alanine substitution at nucleotide 1691) in the gene for factor V (F5), versus 12 of 253 control subjects (4.7%; difference not significant)., Conclusion: In this white population a missense mutation of MTHFR, an insertion mutation of CBS, and a missense mutation of F5 were not found to be associated with an increased risk for preeclampsia, either independently or in combination.

Published
2001
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37. Risk of pre‐eclampsia in patients with a maternal genetic predisposition to common medical conditions: a case–control study.

Author

Gray, KJ, Kovacheva, VP, Mirzakhani, H, Bjonnes, AC, Almoguera, B, Wilson, ML, Ingles, SA, Lockwood, CJ, Hakonarson, H, McElrath, TF, Murray, JC, Norwitz, ER, Karumanchi, SA, Bateman, BT, Keating, BJ, and Saxena, R

Subjects
PREECLAMPSIA, SINGLE nucleotide polymorphisms, CASE-control method, BODY mass index, ALKALINE phosphatase
Abstract

Objective: To assess whether women with a genetic predisposition to medical conditions known to increase pre‐eclampsia risk have an increased risk of pre‐eclampsia in pregnancy. Design: Case–control study. Setting and population: Pre‐eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene‐centric array. Methods: Significant single‐nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome‐wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre‐eclampsia. Odds of pre‐eclampsia were compared across quartiles of the genetic instrument and evaluated for significance. Main outcome measures: Genetic predisposition to medical conditions and relationship with pre‐eclampsia. Results: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre‐eclampsia (DBP, overall OR 1.11, 95% CI 1.01–1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00–1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82–0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early‐onset pre‐eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08–1.56, P = 0.005). For other traits, there was no evidence of an association. Conclusions: These results suggest that the underlying genetic architecture of pre‐eclampsia may be shared with other disorders, specifically hypertension and obesity. A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre‐eclampsia. A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre‐eclampsia. [ABSTRACT FROM AUTHOR]

Published
2021
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38. A search for the gene(s) predisposing to idiopathic clubfoot

Author

Dietz, FR, Cole, WG, Tosi, LL, Carroll, NC, Wemer, RD, Comstock, D, and Murray, JC

Subjects
Clubfoot, Chromosomes, Human, Pair 13, Genes, Humans, Genetic Predisposition to Disease, Chromosomes, Human, Pair 3, Lod Score, Article
Published
2005

39. Genetic studies of body mass index yield new insights for obesity biology

Author

Locke, Adam E, Kahali, Bratati, Croteau-Chonka, Damien C, Doney, Alex S F, He, Bing, Heikkilä, Outi, Hietala, Kustaa, Kytö, Janne, Lahermo, Päivi, Lehto, Markku, Österholm, Anne-May, Parkkonen, Maija, Pitkäniemi, Janne, Rosengård-Bärlund, Milla, Eklund, Niina, Saraheimo, Markku, Sarti, Cinzia, Söderlund, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena M, Tikkanen, Heikki, Tolonen, Nina, Tryggvason, Karl, Tuomilehto, Jaakko, Estrada, Karol, Wadén, Johan, Gill, Geoffrey V, Prior, Sarah, Guiducci, Candace, Mirel, Daniel B, Taylor, Andrew, Hosseini, Mohsen, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Eury, Elodie, Ladenvall, Claes, Alhenc-Gelas, François, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Maestroni, Silvia, Falhammar, Henrik, Gu, Tianwei, Folkersen, Lasse, Möllsten, Anna, Cimponeriu, Dan, Mihai, Ioana, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L, Nelson, Robert G, Kretzler, Matthias, Fraser, Ross M, Colhoun, Helen M, Panduru, Nicolae Mircea, Gu, Harvest F, Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B, Garcia, Melissa E, Waggott, Daryl, Paterson, Andrew D, Savage, David A, Bain, Stephen C, Martin, Finian, Hirschhorn, Joel N, Godson, Catherine, Florez, Jose C, Groop, Per-Henrik, Maxwell, Alexander P, Geller, Frank, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L, Mora, Samia, Giedraitis, Vilmantas, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Chang, Hsing-Y, Demirkan, Ayşe, Den Hertog, Heleen M, Do, Ron, Donnelly, Louise A, Ehret, Georg B, Esko, Tõnu, Feitosa, Mary F, Gigante, Bruna, Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Freitag, Daniel F, Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U, Esko, Tonu, Go, Alan S, Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K E, Mangino, Massimo, Golay, Alain, Mihailov, Evelin, Montasser, May E, Müller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Goodall, Alison H, Service, Susan K, Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Thorleifsson, Gudmar, Gordon, Scott D, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Gorski, Mathias, Been, Latonya F, Bolton, Jennifer L, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doring, Angela, Elliott, Paul, Grabe, Hans-Jörgen, Epstein, Stephen E, Eyjolfsson, Gudmundur Ingi, Goodarzi, Mark O, Grallert, Harald, Gravito, Martha L, Groves, Christopher J, Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A, Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R, Kaleebu, Pontiano, Kastelein, John J P, Khaw, Kay-Tee, Kim, Eric, Grammer, Tanja B, Klopp, Norman, Komulainen, Pirjo, Kumari, Meena, Langenberg, Claudia, Lehtimaki, Terho, Lin, Shih-Yi, Lindstrom, Jaana, Loos, Ruth J F, Mach, François, McArdle, Wendy L, Gräßler, Jürgen, Meisinger, Christa, Mitchell, Braxton D, Muller, Gabrielle, Nagaraja, Ramaiah, Narisu, Narisu, Nieminen, Tuomo V M, Nsubuga, Rebecca N, Olafsson, Isleifur, Ong, Ken K, Palotie, Aarno, Grönberg, Henrik, Papamarkou, Theodore, Pomilla, Cristina, Pouta, Anneli, Rader, Daniel J, Reilly, Muredach P, Ridker, Paul M, Rivadeneira, Fernando, Rudan, Igor, Ruokonen, Aimo, Samani, Nilesh, Fall, Tove, Scharnagl, Hubert, Seeley, Janet, Silander, Kaisa, Stančáková, Alena, Stirrups, Kathleen, Swift, Amy J, Tiret, Laurence, Uitterlinden, Andre G, van Pelt, L Joost, Vedantam, Sailaja, Gusto, Gaëlle, Wainwright, Nicholas, Wijmenga, Cisca, Wild, Sarah H, Willemsen, Gonneke, Wilsgaard, Tom, Wilson, James F, Young, Elizabeth H, Zhao, Jing Hua, Adair, Linda S, Arveiler, Dominique, Haessler, Jeffrey, Assimes, Themistocles L, Bandinelli, Stefania, Bennett, Franklyn, Bochud, Murielle, Boehm, Bernhard O, Boomsma, Dorret I, Borecki, Ingrid B, Bornstein, Stefan R, Bovet, Pascal, Burnier, Michel, Hall, Per, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chen, Yii-Der Ida, Collins, Francis S, Cooper, Richard S, Danesh, John, Dedoussis, George, de Faire, Ulf, Feranil, Alan B, Haller, Toomas, Ferrieres, Jean, Ferrucci, Luigi, Freimer, Nelson B, Gieger, Christian, Groop, Leif C, Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B, Hingorani, Aroon, Hallmans, Goran, Hofman, Albert, Hovingh, G Kees, Hsiung, Chao Agnes, Humphries, Steve E, Hunt, Steven C, Hveem, Kristian, Iribarren, Carlos, Jarvelin, Marjo-Riitta, Jula, Antti, Hartman, Catharina A, Kähönen, Mika, Kaprio, Jaakko, Kesäniemi, Antero, Kivimaki, Mika, Kooner, Jaspal S, Koudstaal, Peter J, Krauss, Ronald M, Kuh, Diana, Kuusisto, Johanna, Kyvik, Kirsten O, Hassinen, Maija, Laakso, Markku, Lakka, Timo A, Lind, Lars, Lindgren, Cecilia M, Martin, Nicholas G, März, Winfried, McCarthy, Mark I, McKenzie, Colin A, Meneton, Pierre, Metspalu, Andres, Moilanen, Leena, Morris, Andrew D, Munroe, Patricia B, Njølstad, Inger, Pedersen, Nancy L, Power, Chris, Pramstaller, Peter P, Price, Jackie F, Psaty, Bruce M, Quertermous, Thomas, Heard-Costa, Nancy L, Rauramaa, Rainer, Saleheen, Danish, Salomaa, Veikko, Sanghera, Dharambir K, Saramies, Jouko, Schwarz, Peter E H, Sheu, Wayne H-H, Shuldiner, Alan R, Siegbahn, Agneta, Spector, Tim D, Helmer, Quinta, Stefansson, Kari, Strachan, David P, Tayo, Bamidele O, Tremoli, Elena, Uusitupa, Matti, van Duijn, Cornelia M, Vollenweider, Peter, Wallentin, Lars, Wareham, 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EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Eriksson, J., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Peacock, M., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., van Meurs JB., Weedon, MN., Wichmann, H., Young, L., Bierut, LJ., Boyd, HA., Econs, MJ., Van T'Hooft, Ferdinand M., Njølstad, Inger, Abecasis, Gonçalo R., Barroso, Inɥ, The MIGEN Consortium, Investigator, Casari, GIORGIO NEVIO, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Landsteiner Laboratory, Clinical Haematology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life 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Investigators, The MuTHER Consortium, The MIGen Consortium, The PAGE Consortium, The ReproGen Consortium, The GENIE Consortium, The International Endogene Consortium, Berndt, Sonja I, Justice, Anne E, Hyppönen, Elina Tuulikki, Epidemiology and Data Science, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes

Subjects
Male, LOCI, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Body Mass Index, Insulin Secretion, Insulin, Age Factor, Adiposity, ddc:616, Adipogenesis, Genetic Predisposition to Disease/genetics, Synapse, 3. Good health, Continental Population Group, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], GENOME-WIDE ASSOCIATIONPROVIDES INSIGHTSGLYCEMIC TRAITSLOCIMETAANALYSISVARIANTSINDIVIDUALSHIPPOCAMPALARCHITECTURETOPIRAMATE, ddc:500, Adipogenesis/genetics, Single Nucleotide/genetics, Age Factors, Continental Population Groups, Energy Metabolism, Europe, Female, Genetic Predisposition to Disease, Glutamic Acid, Humans, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Synapses, Genome-Wide Association Study, Multidisciplinary, genetics [Adiposity], Human, Socio-culturale, genetics [Energy Metabolism], ta3111, genetic, body mass index, obesity, SDG 3 - Good Health and Well-being, GLYCEMIC TRAITS, genetics [Continental Population Groups], Genetic variability, Polymorphism, GENOME-WIDE ASSOCIATION, genetics [Adipogenesis], METAANALYSIS, Genetic association, Adipogenesi, genetics [Quantitative Trait Loci], ta1184, metabolism [Glutamic Acid], ta1182, PATHWAYS, metabolism [Synapses], ta3121, medicine.disease, metabolism [Insulin], Adiposity/genetics, Clinical Medicine, Quantitative Trait Loci/genetics, Body mass index, HUMAN HEIGHT, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Synapses/metabolism, Medizin, Obesity/genetics, Bioinformatics, genetic basis, Obesity/metabolism, genetics [Obesity], body mass index (BMI), genetics [Genetic Predisposition to Disease], ethnology [Europe], 2. Zero hunger, Genetics, ARCHITECTURE, Genetics of obesity, Medicine (all), Single Nucleotide, Polymorphism, Single Nucleotide/genetics, Insulin/metabolism/secretion, Glutamic Acid/metabolism, genetics [Polymorphism, Single Nucleotide], EXPRESSION, Insulin/metabolism, PROVIDES INSIGHTS, genetics [Racial Groups], Biology, Obesity/genetics/metabolism, Europe/ethnology, metabolism [Obesity], Mendelian randomization, medicine, Energy Metabolism/genetics, body mass, genetic analysis, obesity, Klinisk medicin
Abstract

Item does not contain fulltext Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for approximately 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Published
2015
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