Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

Abstract

There are thousands of rare human disorders caused by a single deleterious, protein-coding genetic variant1. However, patients with the same genetic defect can have different clinical presentations2–4, and some individuals carrying known disease-causing variants can appear unaffected5. What explains these differences? Here, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders, such as global developmental delay and autism, often with abnormalities of other organ systems. While the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome wide common variant burden by showing that it is over-transmitted from parents to children with neurodevelopmental disorders in an independent sample of 728 trios from the same cohort. Our common variant signal is significantly positively correlated with genetic predisposition to fewer years of schooling, decreased intelligence, and risk of schizophrenia. We found that common variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, suggesting that common variant risk is not confined to patients without a monogenic diagnosis. In addition, previously published common variant scores for autism, height, birth weight, and intracranial volume were all correlated with those traits within our cohort, suggesting that phenotypic expression in individuals with monogenic disorders is affected by the same variants as the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders typically considered to be monogenic.

Analyses of rare and common alleles in parent-proband trios implicate rare missense variants in SLC6A1 in schizophrenia and confirm the involvement of loss of function intolerant and neurodevelopmental disorder genes

“…Thus, affected carriers of schizophrenia-associated CNVs have been shown to have an elevated burden of common schizophrenia risk alleles as measured by the polygenic risk score (PRS), and this is inversely proportional to the estimated effect size of the implicated CNV 18 . Analogous observations have been made in ASD and DD, where common variant polygenic risk for those disorders has been shown to be over-transmitted from parents to probands, even in those that carry a disorder-associated DNV 20,21 . However, as yet, the relationship between rare exonic DNVs and common allele risk has not been studied in schizophrenia.…”

Genetic risk underlying psychiatric and cognitive symptoms in Huntington’s Disease

“…By contrast, in severe monogenic neurodevelopmental disorders, behavioural phenotypes (such as autistic behaviour and developmental delay) have been shown to be modulated by common genetic variation in the same direction as in the population for the traits examined, with similar effect sizes (R 2 of 0.6-0.8%) to those observed here (31). These results, in conjunction with ours, indicate that even in diseases previously assumed to be entirely attributable to single genetic variants, there is a contribution of polygenic risk in influencing phenotypic presentation (30).…”

Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

“…The common genetic variation affecting these ribosomal protein genes might contribute to the incomplete penetrance and variable expressivity of anemia seen in Diamond-Blackfan anemia patients . Similar effects have been reported in neurodevelopmental disorders, where common genetic variants may influence phenotypic outcomes in patients (Niemi et al, 2018). Non-ribosomal hits in the mRNA metabolism space were also found with both previously established and unknown ties to erythroid-specific phenotypes.…”