Genetic Variants Linked to Intellectual Disability

Pauline Anderson

May 26, 2015

Using genome-wide assays that can detect submicroscopic genomic changes, researchers have found that structural variants in copy number variants (CNVs) are associated with intellectual disability in a general population sample.

The findings shed more light on the genomic basis of intellectual disability, developmental disorders, and neurocognitive and neurobehavioral traits.

But because the CNVs were found in people not necessarily diagnosed with an intellectual disability, the findings raise some ethical issues, according to study author Alexandre Reymond, PhD, director, Center for Integrative Genomics, and associate professor, University of Lausanne, Switzerland.

As biobanks become more common and an increasing number of people donate their DNA, the question becomes whether to inform these volunteers of genetic links that are discovered.

"This is new territory," said Dr Reymond. "Personally, I think we should inform them, but it's still an open debate."

The study was published online May 26 in JAMA.

Duplication or Deletion

CNVs are variations in the number of copies of inherited genetic material. They can be either a duplication (too many copies — for example, 3 instead of 1 each from each parent) or a deletion (too few copies). The more deletions or duplications, the more DNA can be damaged.

CNVs can disrupt transcription on a whole-cell level. For example, they can cause widespread changes in what genes are expressed, and at what level.

Large recurrent CNVs are defined as larger than 500 kilo — or thousand — base pairs (kb); intermediate CNVs are defined as 250 to 500 kb. Most intermediate rare CNVs are thought to be "nondeleterious" to intellectual ability, according to Dr Reymond.

The researchers first studied a large Estonian general population using a random sample of 7877 of the 52,000 DNA samples from the Estonian Genome Center biobank, which houses 5% of the adult Estonian population. General practitioners examined study participants enrolled in the biobank, completed health and lifestyle-related questionnaires, and reported clinical diagnoses.

The investigators identified 56 carriers of recurrent large CNVs associated with known genomic disorders. This represented a rate of 7.1 per 1000 personal genomes assayed (0.7%), or about 1 in every 141 individuals studied.

When they compared this with clinical information on these patients, 70% had no prior knowledge of, or were not clinically documented with, intelligence-related problems. 

Dr Reymond and his colleagues generated a genome-wide map of rare (a frequency of <0.05%) and large autosomal CNVs. From this, they identified 10.5% of the screened general population as carriers.

Compared with the Estonian population, carriers with deletions larger than 250 kb or duplications larger than 1 Mb (million base pairs) showed a statistically significant greater prevalence of intellectual disability (4.3% of deletion carriers, 5.9% of duplication carriers, and 1.7% of the Estonian population).

"That points out that rare CNVs of intermediate size do have an influence of cognition," commented Dr Reymond.

To ensure this wasn't a spurious or chance finding, the researchers looked at educational underachievement as a proxy for intellectual disability. They found the same connection; more carriers didn't graduate from secondary school (33.5% of the deletion carriers, 39.1% of the duplication carriers, and 25.4% of the Estonian population).

Even though earlier studies failed to identify common CNVs as major contributors to heritability, the current results suggest that rare structural variants are associated with complex traits, such as educational attainment and variance in intelligence in population cohorts, the authors write.

British Teens

The researchers also looked at other populations, including a group of British teenagers, but instead of educational attainment, they used scores on the SAT (a test given to adolescents in the United Kingdom). They found that carriers of intermediate-size CNVs had lower SAT scores in English and math than the general population of adolescents.

And they got similar results in a study in Minnesota in the United States, and in Italy.

"We are seeing the same results in different populations using different measures of cognition, and they all point in the same direction," said Dr Reymond.

Deletions had more of an effect in women than men, the researchers noted. Although women are more likely to carry large CNV deletions, they are less likely to show severe clinical symptoms due to these deletions. So whereas men would not have volunteered for the study population if they were diagnosed with a developmental disorder, women with similar deletions may not have been diagnosed and would therefore have remained in the study.

This could explain why more females in the biobank were identified with CNVs, said Dr Reymond.

The authors suggested that while many people with rare CNVs are never clinically diagnosed, their quality of life is negatively affected. Dr Reymond noted that some participants in the study were relieved when told they were carriers.

"The interesting thing is that they were actually pleased" because it helped explain some of the difficulties or struggles they had faced in life, he said.

The research suggests that several genes are important to intelligence and that there's no single "intelligence gene," said Dr Reymond.

Tailored Interventions

In an accompanying editorial, James Lupski, MD, PhD, Department of Molecular and Human Genetics, Department of Pediatrics, and Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, outlined the importance of this new information.

"With the recognition of a potentially causal mutation in an individual, tailored behavioral and educational interventions could be initiated with patients and family that could improve educational outcomes," Dr Lupski writes.

"Although changing a person's genome is not possible, identifying those with CNVs related to cognitive phenotypes could provide an opportunity to help them reach their fullest potential."

Dr Lupski noted that using genome analyses to identify disease-associated variations, including CNVs, expands the scope of the genetic information that can be obtained from a family history. "Such genomic studies can identify new mutations that may be relevant to optimizing cognitive performance and health."

Genomic studies may become a part of common medical practice, potentially assisting in the formulation of differential diagnoses, he added.

However, more work remains, Dr Lupski concludes. "For intellectual disability, this includes more robust characterization of the specific clinical phenotypes and range of variation that can be observed in those phenotypes, with locus-specific genetic and genomic changes."

The study is funded by support to individual investigators from a scholarship from the Swiss Scientific Exchange New Member State of the European Union Program; a PhD studentship from the Wellcome Trust; and a Bursary Professor of the Swiss National Science Foundation (SNSF). It was also supported by two SNSF grants, a specific 16p11.2 SNSF Sinergia grant, the Simons Foundation Autism Research Initiative, Leenaards Foundation Prizes, European Commission Framework Program 7 grants, Center of Excellence in Genomics (EXCEGEN) and University of Tartu, Estonian Research Council Grant, US Public Health Service grants from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the National Institute of Mental Health. Dr Reymond has disclosed no relevant financial relationships. Dr Lupski reports that he owns stock in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen Inc, is a member of the scientific advisory board of Baylor Miraca Genetics Laboratories, and is a coinventor on US and European patents related to molecular diagnostics. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Baylor Miraca Genetics Laboratory.

JAMA. Published online May 26, 2015. Abstract Editorial


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