Environmental risk factors for autism: Do they help cause de novo genetic mutations that contribute to the disorder?

Abstract

Recent research has discovered that a number of genetic risk factors for autism are de novo mutations. Advanced parental age at the time of conception is associated with increased risk for both autism and de novo mutations. We investigated the hypothesis that other environmental factors associated with increased risk for autism might also be mutagenic and contribute to autism by causing de novo mutations. A survey of the research literature identified 9 environmental factors for which increased pre-conceptual exposure appears to be associated with increased risk for autism. Five of these factors – mercury, cadmium, nickel, trichloroethylene, and vinyl chloride – are established mutagens. Another four – including residence in regions that are urbanized, located at higher latitudes, or experience high levels of precipitation – are associated with decreased sun exposure and increased risk for vitamin D deficiency. Vitamin D plays important roles in repairing DNA damage and protecting against oxidative stress – a key cause of DNA damage. Factors associated with vitamin D deficiency will thus contribute to higher mutation rates and impaired repair of DNA. We note how de novo mutations may also help explain why the concordance rate for autism is so markedly higher in monozygotic than dizygotic twins. De novo mutations may also explain in part why the prevalence of autism is so remarkably high, given the evidence for a strong role of genetic factors and the low fertility of individuals with autism – and resultant selection pressure against autism susceptibility genes. These several lines of evidence provide support for the hypothesis, and warrant new research approaches – which we suggest – to address limitations in existing studies. The hypothesis has implications for understanding possible etiologic roles of de novo mutations in autism, and it suggests possible approaches to primary prevention of the disorder, such as addressing widespread vitamin D deficiency and exposure to known mutagens.

Introduction

Many lines of research, including family and twin studies, as well as genetic linkage and association studies, indicate that genetic factors are important in the etiology of autism [1], [2], [3]. Recent research has discovered that a number of the genetic risk factors for autism are de novo mutations [3], [4], [5], [6], [7]. This research includes, for example, multiple reports of de novo mutations in genes that either code for, or regulate expression of, genes involved in the structure or function of synapses [6], [8]. Smith et al. [3] review evidence for mitochondrial as well as nuclear genomic instability in autism, and they note the importance of investigating whether environmental factors, such as reactive oxygen species that can cause mutations, may play a role in producing this instability.

If de novo mutations are indeed important contributing factors in autism, it could help to explain several puzzling facts about the disorder. Thus, for example, autism is surprisingly common for a disorder that is so disabling and is associated with such low rates of marriage and fertility, yet is estimated to have an extremely high heritability – over 90% based on twin concordance rates [9]. De novo mutations could help explain this puzzle if a constant influx of such new mutations into a population helps offset the continual elimination of autism susceptibility genes from the population because of low average fertility rates in individuals with autism. If de novo mutations play a significant role in a disorder, it will also tend to produce a much higher concordance rate in monozygotic than dizygotic twins, because the same de novo mutation will typically be inherited by both members of a monozygotic twin pair, but only very rarely by both members of a dizygotic twin pair. It is notable that this is the pattern of twin concordance rates that is found in autism [1], [5], [10]. Rutter and Simonoff [2] reviewed the results of the three twin studies of autism that used samples representative of the general population; the pairwise concordance rates for monozygotic twins in these three studies [9], [11], [12] were, respectively, 36%, 69%, and 91%, whereas in each study the concordance rate for dizygotic twins was 0%.

Another striking finding on autism is the strong tendency for autism risk to increase with the age of the parents – particularly the father – at the time of conception. For example, Croen et al. [13] found the relative risks of autism associated with advanced maternal and paternal age to be 1.18 and 1.34, respectively. Reichenberg et al. [14] found that risk for autism spectrum disorders (ASD) was 5.75 times higher if individuals were born to fathers ⩾40 years of age, rather than 30 years or younger.

That parental age may contribute to increased autism risk by causing such de novo mutations is suggested by evidence that advanced parental age contributes significantly to the frequency of de novo mutations [15], [16], as well as to risk for autism. This is particularly true in the male germline, as the lifelong production of sperm cells offers significantly more opportunities for mutations than is the case for ova. Paternal age effects and paternally linked mutations have been reported in a number of genetic disorders, including achondroplasia, Apert syndrome, Crouzon syndrome, and Pfeiffer syndrome [16].

These findings suggested to us the hypothesis that other environmental factors may also be associated with increased risk for autism, at least in part, because they contribute to de novo mutations. As an initial test of this hypothesis, we surveyed the research literature to identify environmental factors for which increased pre-conceptual exposure appears to be associated with increased risk for autism. We then examined whether these risk factors for autism are likely to contribute to higher rates of de novo mutations.