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GWAS Reveals Common, Polygenic Contributors to Neurodevelopmental Disorders

NEW YORK (GenomeWeb) – A team led by researchers at the Wellcome Trust Sanger Institute has garnered evidence suggesting common genetic variants can modify an individual's risk of developing rare, severe neurodevelopmental conditions.

"We discovered that common variants that work together to influence common diseases such as schizophrenia also seem to contribute to rare developmental disorders," first author Mari Niemi, a Ph.D. student in senior author Jeffrey Barrett's Sanger Institute lab, said in a statement. "These variants could lead to changes during brain development, that could cause a range of common or rare conditions."

In a study published online today in Nature, Niemi, Barrett, and their colleagues estimated that common, inherited variants explain almost 8 percent of risk variance for rare neurodevelopmental conditions such as global developmental delay, intellectual disability, or cognitive impairment.

"Our findings suggest that fully understanding the genetic architecture of neurodevelopmental disorders will require considering the full spectrum of alleles, from those unique to an individual to those shared across continents," the authors wrote. 

The team performed a genome-wide association study involving 6,987 genotyped and phenotyped children with severe neurodevelopmental conditions, enrolled through the Deciphering Developmental Disorders (DDD) study, and almost 9,300 ancestry-matched, unaffected controls. The results revealed common variant shifts in the DDD cohort, though no individual SNPs showed genome-wide significant ties to the conditions.

From such data, the researchers came up with a polygenic risk score for severe neurodevelopmental disorders, using it to replicate their results in a validation cohort that included another 728 children with neurodevelopmental delay and their parents and to search for overlap with variants implicated in other traits or conditions.

When the team compared the neurodevelopmental disorder-related common variant score to data from prior association studies on anthropometric traits, educational outcomes, or neuropsychiatric conditions, it saw overlaps with schizophrenia-related variants. On the other hand, traits such as educational attainment ticked up as the neurodevelopment disorder score dipped lower.

The researchers went on to establish common variant-based polygenic scores for subsets of individuals with neurodevelopmental disorders, including the 16 percent of cases involving autism spectrum disorder. From these and other analyses, they concluded that common variants contributed to overall neurodevelopmental disorder risk and the way that the conditions manifested themselves, both in the cases that did or did not include diagnoses based on rarer, single gene mutations.

"There is … emerging evidence that the cumulative effect of common variants can modify the penetrance of rare variants in complex phenotypes such as educational attainment, schizophrenia, and breast cancer," the authors wrote. "Here we have shown that the same interplay between rare and common variation exists even in severe neurodevelopmental disorders that are typically presumed to be monogenic."