29633
The Differential Effect of Gene Dosage on Autism Risk and General Intelligence

Poster Presentation
Friday, May 3, 2019: 5:30 PM-7:00 PM
Room: 710 (Palais des congres de Montreal)
E. A. Douard1,2, C. Schramm1,2,3, A. Zeribi1, S. Nowak1,2, M. P. Poulin-Lord1,2, M. Jean Louis1, M. Auger1, T. Bourgeron4, T. Paus5,6, Z. Pausova7,8, A. Labbe9, C. Greenwood3,10, G. Huguet1,2 and S. Jacquemont11,12, (1)Research Center of UHC Sainte-Justine, Montreal, QC, Canada, (2)University of Montreal, Montreal, QC, Canada, (3)Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada, (4)University Denis Diderot Paris 7, Paris, France, (5)Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada, (6)Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada, (7)University of Toronto, Toronto, ON, Canada, (8)Hospital for Sick Children, Toronto, ON, Canada, (9)Département de Sciences de la Décision, HEC Montreal, Montreal, QC, Canada, (10)Departments of Human Genetics and Oncology, McGill University, Montreal, QC, Canada, (11)Service of Medical Genetics, CHUV, Lausanne, Switzerland, (12)CHU Sainte Justine, University of Montreal, Montreal, QC, Canada
Background:

Whole-genome analysis have estimated that rare mutations in over 1,000 genes may contribute to autism risk. Several studies have identified robust associations between rare Copy Number Variants (CNVs) and the diagnosis of Autism Spectrum Disorder (ASD). More specifically, a recent publication has shown that de novo mutations are associated with lower Intelligence Quotient (IQ) and a blunted autism profile. But almost nothing is known on cognitive and behavioral traits affected by rare CNVs and how these alterations lead to a diagnosis of autism.

We hypothesize that classes of mutations such as haploinsufficient ones versus duplications, have differential impacts on cognitive and behavioral traits, thus leading to a diagnosis of ASD by different mechanisms. To better understand the effect of CNVs, our laboratory recently developed models trained in the general population to estimate their effect size on non-verbal IQ (NVIQ) using constraint scores.

Objectives:

Understand the differential effect of haploinsufficiency and duplications on cognition, behavior and autism risk using autistic and general populations.

Methods:

We identified all CNVs ≥ 50Kb in 2,590 simplex ASD families in the Simon Simplex Collection and in 2,702 individuals from general population (Imagen and Saguenay Youth Study cohorts) following detection standard detection pipelines. We used statistical models integrating genomic and functional annotations (such as probability to be Loss of function Intolerant (pLI) score) to estimate the effects of deletions and duplications on autism risk and NVIQ.

Results:

We demonstrate that genome-wide deletions and duplications have a quantifiable effect on NVIQ and autism risk. Our model estimates that deletions and duplications decrease NVIQ respectively by 2.6 points per unit of pLI score (SE=0.42; P=7×10-10) and by 0.9 points per unit of pLI score (SE=0.29; P=2×10-3). This effect is identical in autistic and general populations for deletions but not for duplications.

We also show that deletions are significantly overrepresented in autistic probands compared to unaffected siblings or general population (both OR=1.3 per unit of pLI, 95%CI=[1.2;1.5], P=8×10-5). However, after adjusting for the effect on NVIQ, deletions are no more enriched in autism compared to general population. Conversely, duplications are significantly overrepresented in autism when comparing to unaffected siblings and general population (both OR=1.2 per unit of pLI, 95%CI=[1.1;1.4], P<4×10-5). This excess of duplications remains after NVIQ adjustment.

Conclusions:

Although deletions are highly overrepresented in individuals with a diagnosis of autism, it is probable that the general effect of haploinsufficiency is unrelated to core symptoms of ASD. Instead, our results suggest that haploinsufficiency increases the probability of clinical referral due to a pervasive impact on IQ. In contrast, the association between duplications and autism diagnosis is not explained by their effect on intelligence. To understand mechanisms underlying this association, we are investigating the effect of duplication on ASD severity, social responsiveness, and other measures of psychopathology. This study represents a new framework to study variants in ASD and better characterize the heterogeneity observed in clinic.

See more of: Clinical Genetics
See more of: Clinical Genetics