The joint effect of air pollution exposure and copy number variation on risk for autism

Autor: Yunin Ludena-Rodriguez, Molly A. Hall, Santhosh Girirajan, Marylyn D. Ritchie, Dokyoon Kim, Kyoungmi Kim, Heather E. Volk, Irva Hertz-Picciotto, Debashis Ghosh, Scott B. Selleck, Rebecca J. Schmidt, Robin L Hansen, Shefali S. Verma, Sarah A. Pendergrass
Rok vydání: 2017
Předmět:
Zdroj: Autism Research. 10:1470-1480
ISSN: 1939-3792
DOI: 10.1002/aur.1799
Popis: Autism is a behavioral disorder that has been the subject of extensive genetic studies (Jeste and Geschwind, 2014). The incidence of ASD in the U.S., currently estimated at 1 in 56 children {Developmental Disabilities Monitoring Network Surveillance Year Principal, 2014 #41}, makes this set of disorders a public health, educational, and economic concern. While autism has been determined to be highly heritable, recent estimates have elevated the proportion of variance attributable to environment. Early family studies of twins estimated the proportion of genetic contribution to autism as high as 90% [see for example, (Bailey et al., 1995, Folstein and Rutter, 1977, Lichtenstein et al., 2010)]. A more recent assessment of twins, while supporting a substantial genetic component, also indicated significant contributions from shared environment (Hallmayer et al., 2011). A large longitudinal study of all births in Sweden between 1982 and 2006 that included more than 14,000 individuals diagnosed with ASD, provided evidence that genetic and environmental contributors to autism are essentially equal, each accounting for about 50% of the variability (Sandin et al., 2014). A parallel study of this same cohort that examined SNP variants in some 3000 subjects, arrived at similar estimates of the heritability proportion (52%), and indicated that common variants comprise the majority of genetic risk for autism (Gaugler et al., 2014). The best estimates at present, therefore, indicate that the etiological architecture of autism includes essentially equal contributions from environment and DNA sequence variation, and both common and rare genomic variants play a role in disease risk and severity. While these studies have established the importance of both genetic and environmental factors in autism, direct measures of their relative contributions and moreover, of the interactions between them are lacking. Copy number variants are one type of genomic change that contributes to autism susceptibility. The pioneering study by Sebat and colleagues found a ten-fold higher frequency of large and rare de novo variants in children with autism compared to control subjects (Sebat et al., 2007). Subsequent work confirmed these findings (Pinto et al., 2010) and revealed that copy number burden represented in large CNVs correlated with the severity of the phenotypes found in children with neurobehavioral disorders (Girirajan et al., 2011). Genome-wide analysis of both rare and common CNVs demonstrated that autism is associated with increased levels of copy number load, measured as base pairs of change, with a preponderance of duplications (Girirajan et al., 2013). In addition, the level of copy number load negatively correlated with measures of communication and social skills (Girirajan et al., 2013). Further, whole exome sequence analysis has shown that children with autism inherit more CNVs than their unaffected siblings (Krumm et al., 2013). There is therefore good evidence that total genomic copy number burden is a meaningful measure of genomic change that contributes to autism susceptibility and a good sensor for assessing genome-environment interactions. Phenotypic variation is an expression of several determinants, including genetic variation, environmental exposure, and the interactions between genetic variants and the environment. The magnitude and frequency of gene-environment interactions are largely unknown, and therefore the degree to which environmental impact coupled with genetic variation can explain the so-called “missing heritability” is unresolved. Current genetic studies of complex disorders often assume no appreciable gene-environment interactions, an assumption that has not been validated by experiment (Gaugler et al., 2014). The paucity of gene-environment interaction measures has a simple origin, it requires detailed genetic and environmental data for the same group of individuals, an expensive and time consuming endeavor. A growing body of evidence supports specific environmental contributors to autism susceptibility. In particular, prenatal air pollution exposure has come to the forefront of environmental ASD risk factors as 11 studies from the United Sates, using different study designs and methods, all suggest increased risk with increasing exposure.(Becerra et al., 2013, Kalkbrenner et al., 2010, Kalkbrenner et al., 2015, Raz et al., 2015, Roberts et al., 2013, Talbott et al., 2015a, Talbott et al., 2015b, Volk et al., 2011, Volk et al., 2013, von Ehrenstein et al., 2014, Windham et al., 2006) Criteria air pollutants, including nitrogen dioxide (NO2), particulate matter less than 10 and less than 2.5 microns in diameter (PM10, PM2.5), and ozone, are routinely monitored by the Environmental Protection Agency (EPA) and exposure to both NO2 and PM have been associated with ASD in populations from both Northern and Southern California(Becerra et al., 2013, Kalkbrenner et al., 2015, Volk et al., 2013), North Carolina (Kalkbrenner et al., 2010, Kalkbrenner et al., 2015) West Virginia (Kalkbrenner et al., 2010), Pennsylvania (Talbott et al., 2015b), and in the nation-wide Nurses Health Study(Raz et al., 2015). When studies have attempted to identify critical time periods of exposure, pregnancy and potentially the latter half of pregnancy appear the most important(Weisskopf et al., 2015). Few studies have attempted to include multiple criteria pollutants in the same model, though in the analyses that do, effects of NO2, PM2.5, and ozone persist.(Becerra et al., 2013, Volk et al., 2013) We are aware of only one other paper to date, that has examined genetic susceptibility together with air pollution exposure on ASD risk (Volk et al., 2014). This study sought to examine the joint effect of genetic susceptibility for ASD, as reflected in copy number variation, and air pollution exposure on risk of ASD in the Childhood Autism Risks from Genetics and Environment (CHARGE) study.
Databáze: OpenAIRE
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