Orofacial clefts (OFCs) affect approximately 1.7 of every 1000 live births worldwide, making them among the most common birth defects. For the approximately 600 babies born with OFCs each year in Canada, multidisciplinary surgical and nonsurgical care is needed until adulthood. In addition to psychological effects suffered by the affected children and their families, OFCs have been associated with increased risk of death from birth to age 55. OFCs clearly bring a substantial burden on affected individuals and their families and substantial costs to the health care system. Despite research efforts, the causes of OFCs are still largely unknown. Maternal environmental exposures in combination with maternal genetic effects can disrupt important processes involved in facial development. Hence, maternal genetic effects involved in OFC aetiology could act only or more strongly under specific environments. A GWAS data on over 2000 parent-offspring trios from the GENEVA (Gene-Environment Association Studies) Oral Clefts project found weak evidence for maternally mediated genetic effects but did not take the maternal environment into account. The overall goal of our study is to identify maternal genetic effects influencing OFC risk acting in specific environmental conditions. Our specific objectives and working hypotheses are: 1. To genotype 545 trios (child and parents) from two ongoing European studies (ITALCLEFT and EUROCRAN) and combine them to the publicly available GENEVA trios to perform a genome-wide association study (GWAS) of maternally mediated main genetic effects. 2. To perform a GWAS of the interaction between maternally mediated genetic effects and key environmental factors, including maternal smoking and multivitamin exposure. 3. To perform a GWAS of the interaction between maternal and child genetic effects, taking the environment into account. We will use strict quality control procedures to combine existing and new genotype data. The ITALCLEFT and EUROCRAN samples have successfully been used to replicate OFC GWAS significant results. Maternal genetic effects and combined mother-child genetic effects will be tested using existing specialized association tests. Interactions will be assessed by stratification first. We will also extend and implement a recently proposed approach to detect joint effects among maternal variants, child variants, and maternal environmental exposures. Our research team brings together the extensive expertise in genetic epidemiology and biostatistics of the PI, Dr. Roy-Gagnon, to that of co-applicant Dr. Little, a world leader in Human Genome Epidemiology who has been studying the epidemiology of OFCs for over 15 years. Collaborators Drs. Rubini, Mossey and Steegers-Theunissen are also experts on OFCs and PIs of the European studies. Our project will be the first to investigate maternal gene-environment interactions at the genome-wide level. The environment is more easily modifiable compared to genetic factors. Our study could thus lead to important public health applications in terms of designing effective, targeted prenatal interventions in Canada and elsewhere.
Scheda prodotto non validato
Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo
|Autori:||Roy Gagnon, Marie Hélène; Rubini, Michele|
|Titolo:||Environment-specific maternal genetic effects in orofacial clefts|
|Data di pubblicazione:||2017|
|???metadata.dc.type.research???:||Locale (anche progetti interni a UNIFE)|
|Appare nelle tipologie:||08.1 Coordinamento Prog.Ricerca Naz. ed Internaz.|