Examining Genetic, Environmental Factors in Childhood-Onset Neuropsychiatric Disorders

Autism spectrum disorder, persistent tic disorders such as Tourette’s syndrome, chronic tic disorder, and obsessive-compulsive disorder represent a significant public health burden in the United States and internationally.

Autism spectrum disorders (ASDs), Tourette’s syndrome (TS) and chronic tic disorder (CT) have their onset during childhood and adolescence, as do about 50% of obsessive-compulsive disorder (OCD) cases. ASD, TS/CT, and OCD may overlap in certain aspects of their phenomenology and can co-occur in affected individuals and in families. There is also evidence that TS/CT and OCD share common genetic roots.

The origin of these childhood-onset neuropsychiatric disorders is complex, with contributions from both genetic and environmental risk factors. Previous studies have provided valuable information about their etiology through reports on heritability, familial recurrence risk, and environmental risk factors.

However, most of these earlier studies used small samples derived from specialty clinics, which may include more severe cases and multiply-affected families. Thus, lower precision, conflicting results between studies, and lack of generalizability may inhibit a robust understanding of etiology.

As a result, researchers have recently turned to national health registries available in countries such as Denmark and Sweden to study the etiology of ASD, TS/CT, OCD, and other psychiatric disorders.

These registries contain demographic and health information on all healthcare-seeking individuals, which comprise the majority of the population in the setting of free nationalized healthcare. These population-based epidemiological samples are large, inclusive of patients with various levels of severity, and allow for an assessment of risk factors in psychiatric illness with high precision and much less bias.

It is recognized that the risk for TS/CT and OCD among individuals with family members affected by these disorders is higher than the risk in the general population. However, early family-based studies attempting to quantify this familial recurrence risk varied widely in their estimates.

In contrast the Danish registries, which from a total population of more than 1.7 million individuals born between 1980 and 2007, included 5,596 individuals diagnosed with TS/CT and 6,191 individuals diagnosed with OCD.

In this large population, the prevalence of each disorder was less than 1%. However, an individual with a sibling diagnosed with TS/CT had nearly a 10% chance of also having TS/CT. For OCD, the risk was 4%. Individuals with a parent diagnosed with TS/CT had a 19% chance of having TS/CT, and those with a parent diagnosed with OCD had a 4% chance of having OCD. Having a family member with TS/CT was also a strong risk factor for developing OCD and vice versa — a finding that supports a relationship between these disorders.1

National health registries have also been used to confirm or refute the contribution of specific environmental risk factors in childhood-onset neuropsychiatric disorders. For example, since in vitro fertilization (IVF) has become more common around the same time the prevalence of ASD has increased, researchers used the Swedish national health registries to assess whether an association exists between the two.

This study included more than 2.5 million infants, of whom more than 30,000 were conceived by IVF and of whom nearly 7,000 were later diagnosed with an ASD. IVF was not a risk factor for ASDs, the researchers found, though it was associated with a very small increased risk for mental retardation.2

In addition, early studies suggested that advancing paternal age may be a risk factor for ASD, leading to the hypothesis that de novo genetic mutations (more common with older paternal age) may contribute to risk for ASDs. Using the Swedish registries, it was recently confirmed in a cohort of more than 1 million individuals (and 1,000 ASD cases) that advanced paternal age is a risk factor for ASDs.3

A subsequent study, including nearly 6,000 cases of ASDs in the Swedish registries, showed that advanced grandpaternal age is also a risk factor and that risk for ASDs may develop over generations, perhaps in part due to the accumulation of de novo mutations.4

Researchers are also using novel laboratory-based methods to better understand childhood-onset neuropsychiatric disorders. For example, recent large-scale genetic studies support the role of de novo mutations in risk for ASDs.5

A recent laboratory-based study including 617 TS cases and 1,061 OCD cases looked at single nucleotide polymorphisms across the genome using Genome-wide Complex Trait Analysis to determine the heritability of these disorders.

The researchers found a heritability of 58% for TS and 37% for OCD, consistent with results from previous family-based studies. The study also indicated that much of the genetic risk for TS and OCD lies in common genetic variants. Moreover, there was a genetic correlation of 0.41 between TS and OCD, providing laboratory-based evidence of a genetic relationship between these disorders.6

In summary, population-based registry resources and novel molecular genetic tools provide new robust methods of investigating the etiology of childhood-onset neuropsychiatric disorders. These data provide clinical information that can be used by clinicians to counsel families with or at risk for the disorders, as well as provide insight into directions for future research.

Dorothy Grice, MD, is a psychiatry professor at the Icahn School of Medicine at Mount Sinai in New York. She is also chief of the Obsessive-Compulsivie and Related Disorders Program there. She is chairing a symposium on this topic at the American Association of Child & Adolescent Psychiatry Annual Meeting on Oct. 22.


  1. Browne HA et al. JAMA Psychiatry. In Press.
  2. Sandin S et al. “Autism and mental retardation among offspring born after in vitro fertilization.” JAMA. 2013; 310(1):75-84.
  3. Hultman CM et al. “Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies.” Mol Psychiatry. 2011; 16(12):1203-1212.
  4. Frans EM et al. “Autism risk across generations: a population-based study of advancing grandpaternal and paternal age.” JAMA Psychiatry. 2013; 70(5):516-521.
  5. Buxbaum JD et al. “The autism sequencing consortium: large-scale, high-throughput sequencing in autism spectrum disorders.” Neuron. 2012; 76(6):1052-1056.
  6. Davis LK et al. Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genet. 2013; 9(10):e1003864