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ABSTRACT: There is a large literature showing the detrimental effects of prenatal smoking on birth and childhood health outcomes. It is somewhat unclear though, whether these effects are causal or reflect other characteristics and choices by mothers who choose to smoke that may also affect child health outcomes or biased reporting of smoking. In this paper we use genetic markers that predict smoking behaviors as instruments to address the endogeneity of smoking choices in the production of birth and childhood health outcomes. Our results indicate that prenatal smoking produces more dramatic declines in birth weight than estimates that ignore the endogeneity of prenatal smoking, which is consistent with previous studies with non-genetic instruments. We use data from two distinct samples from Norway and the United States with different measured instruments and find nearly identical results. The study provides a novel application that can be extended to study several behavioral impacts on health and social and economic outcomes.
Biodemography and Social Biology 01/2011; 57(1):3-32. · 0.52 Impact Factor
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Terri H Beaty,
Jeffrey C Murray,
Mary L Marazita,
Ronald G Munger,
Ingo Ruczinski Jacqueline B Hetmanski,
Kung-Yee Liang,
Tao Wu,
Tanda Murray,
M Daniele Fallin,
Richard A Redett, [......],
Lian Ma,
L Leigh Field,
Lawrence Brody,
Faith Pangilinan,
James L Mills,
Anne M Molloy,
Peadar N Kirke,
James M Scott,
Mauricio Arcos-Burgos,
Alan F Scott
Nature Genetics 08/2010; 42(8):727. · 35.53 Impact Factor
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Terri H Beaty,
Jeffrey C Murray,
Mary L Marazita,
Ronald G Munger,
Ingo Ruczinski,
Jacqueline B Hetmanski,
Kung Yee Liang,
Tao Wu,
Tanda Murray,
M Daniele Fallin, [......],
L Leigh Field,
Lawrence Brody,
Faith Pangilinan,
James L Mills,
Anne M Molloy,
Peadar N Kirke,
John M Scott,
James M Scott,
Mauricio Arcos-Burgos,
Alan F Scott
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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.
Nature Genetics 06/2010; 42(6):525-9. · 35.53 Impact Factor
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Lina M Moreno,
Maria Adela Mansilla,
Steve A Bullard,
Margaret E Cooper,
Tamara D Busch,
Junichiro Machida,
Marla K Johnson,
David Brauer,
Katherine Krahn,
Sandy Daack-Hirsch, [......],
Rolv T Lie,
Astanand Jugessur,
Allen J Wilcox,
Peter Chines,
Elizabeth Pugh,
Kim Doheny,
Mauricio Arcos-Burgos,
Mary L Marazita,
Jeffrey C Murray,
Andrew C Lidral
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ABSTRACT: Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5' and 3' of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.
Human Molecular Genetics 09/2009; 18(24):4879-96. · 7.64 Impact Factor
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ABSTRACT: Cleft lip with or without cleft palate is the most common facial birth defect and it is caused by a complex interaction between genetic and environmental factors. The purpose of this review is to provide an overview of the spectrum of the genetic causes for cleft lip and cleft palate using both syndromic and nonsyndromic forms of clefting as examples. Although the gene identification process for orofacial clefting in humans is in the early stages, the pace is rapidly accelerating. Recently, several genes have been identified that have a combined role in up to 20% of all clefts. While this is a significant step forward, it is apparent that additional cleft causing genes have yet to be identified. Ongoing human genome-wide linkage studies have identified regions in the genome that likely contain genes that when mutated cause orofacial clefting, including a major gene on chromosome 9 that is positive in multiple racial groups. Currently, efforts are focused to identify which genes are mutated in these regions. In addition, parallel studies are also evaluating genes involved in environmental pathways. Furthermore, statistical geneticists are developing new methods to characterize both gene-gene and gene-environment interactions to build better models for pathogenesis of this common birth defect. The ultimate goal of these studies is to provide knowledge for more accurate risk counseling and the development of preventive therapies.
Seminars in Orthodontics 07/2008; 14(2):103-114.
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ABSTRACT: Non-syndromic cleft lip with or without cleft palate (NSCLP) results from the complex interaction between genes and environmental factors. Candidate gene analysis and genome scans have been employed to identify the genes contributing to NSCLP. In this study, we evaluated the 16q24.1 chromosomal region, which has been identified by multiple genome scans as an NSCLP region of interest. Two candidate genes were found in the region: interferon regulatory factor 8 (IRF8) and cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2). Initially, Caucasian and Hispanic NSCLP multiplex families and simplex parent-child trios were genotyped for single nucleotide polymorphisms (SNPs) in both IRF8 and CRISPLD2. CRISPLD2 was subsequently genotyped in a data set comprised of NSCLP families from Colombia, South America. Linkage disequilibrium analysis identified a significant association between CRISPLD2 and NSCLP in both our Caucasian and Hispanic NSCLP cohorts. SNP rs1546124 and haplotypes between rs1546124 and either rs4783099 or rs16974880 were significant in the Caucasian multiplex population (P=0.01, P=0.002 and P=0.001, respectively). An altered transmission of CRISPLD2 SNPs rs8061351 (P=0.02) and rs2326398 (P=0.06) was detected in the Hispanic population. No association was found between CRISPLD2 and our Colombian population or IRF8 and NSCLP. In situ hybridization showed that CRISPLD2 is expressed in the mandible, palate and nasopharynx regions during craniofacial development at E13.5-E17.5, respectively. Altogether, these data suggest that genetic variation in CRISPLD2 has a role in the etiology of NSCLP.
Human Molecular Genetics 10/2007; 16(18):2241-8. · 7.64 Impact Factor
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ABSTRACT: Orofacial clefts are common birth defects with a known genetic component to their etiology. Most orofacial clefts are nonsyndromic, isolated defects, which can be separated into two different phenotypes: (1) cleft lip with or without cleft palate and (2) cleft palate only. Both are genetically complex traits, which has limited the ability to identify disease loci or genes. The purpose of this review is to summarize recent progress of human genetic studies in identifying causal genes for isolated or nonsyndromic cleft lip with or without cleft palate.
The results of multiple genome scans and a subsequent meta-analysis have significantly advanced our knowledge by revealing novel loci. Furthermore, candidate gene approaches have identified important roles for IRF6 and MSX1. To date, causal mutations with a known functional effect have not yet been described.
With the implementation of genome-wide association studies and inexpensive sequencing, future studies will identify disease genes and characterize both gene-environment and gene-gene interactions to provide knowledge for risk counseling and the development of preventive therapies.
Current Opinion in Pediatrics 01/2006; 17(6):731-9. · 2.83 Impact Factor
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ABSTRACT: Non-syndromic cleft lip with or without cleft palate (CL/P) is a genetically complex birth defect, with a prevalence from 1/500 to 1/1,000 live births. Evidence from linkage and linkage disequilibrium studies is contradictory suggesting that heterogeneity between study populations may exist. A recent report of a genome widescan in 92 sib pairs from the United Kingdom revealed suggestive linkage to 10 loci [Prescott et al., 2000]. The purpose of this study is to replicate those results and evaluate additional candidate genes in 49 Colombian and 13 Ohio families. Genotypes were obtained for STRPs at 1p36, 2p13 (TGFA), 4p16 (MSX1), 6p23-25, 6q25-27, 8q23-24, 11p12-q13, 12q13, 14q24 (TGFB3), 16q22-24, 17q12-21 (RARA), and Xcen-q21. Linkage was performed using parametric (dominant and recessive models) and non-parametric (GenehunterNPL and SimIBD) analyses. In addition, heterogeneity was analyzed using GenehunterHLOD, and association determined by the TDT. The Colombian families showed significant SimIBD results for 11p12-q13 (P = 0.034), 12q13 (P = 0.015), 16q22-24 (0.01), and 17q12-21 (0.009), while the Ohio families showed significant SimIBD results for 1p36 (P = 0.02), TGFA (P = 0.005), 6p23 (P = 0.004), 11p12-q13 (P = 0.048) and significant NPL results for TGFA (NPL = 3.01, P = 0.009), 4p16 (MNPL = 2.07, P = 0.03) and 12q13 (SNPL = 3.55, P = 0.007). Significant association results were obtained only for the Colombian families in the regions 1p36 (P = 0.046), 6p23-25 (P = 0.020), and 12q13 (P = 0.046). In addition several families yielded LOD scores ranging from 1.09 to 1.73, for loci at 4p16, 6p23-25, 16q22-24, and 17q13. These results confirm previous reports for these loci. However, the differences between the two populations suggest that population specific locus heterogeneity exists. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.
American Journal of Medical Genetics Part A 04/2004; 125A(2):135-44. · 2.39 Impact Factor
