Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants

Pizzo, Lucilla; Jensen, Matthew; Polyak, Andrew; Rosenfeld, Jill A.; Männik, Katrin; Krishnan, Arjun; McCready, Elizabeth; Pichon, Olivier; Caignec, Cédric Le; Dijck, Anke Van; Pope, Kate; Voorhoeve, Els; Yoon, Jiwon; Stankiewicz, Paweł; Cheung, Sau Wai; Pazuchanics, Damian; Huber, Emily; Kumar, Vijay; Kember, Rachel L.; Mari, Francesca; Currò, Aurora; Castiglia, Lucia; Galesi, Ornella; Avola, Emanuela; Mattina, Teresa; Fichera, Marco; Mandarà, Luana; Vincent, Marie‐Françoise; Nizon, Mathilde; Mercier, Sandra; Bénéteau, Claire; Blesson, Sophie; Martin‐Coignard, Dominique; Mosca-Boidron, Anne Laure; Caberg, Jean Hubert; Bućan, Maja; Zeesman, Susan; Nowaczyk, Małgorzata J.M.; Lefebvre, Mathilde; Faivre, Laurence; Callier, Patrick; Skinner, Cindy; Keren, Boris; Charles, Perrine; Prontera, Paolo; Marle, Nathalie; Renieri, Alessandra; Reymond, Alexandre; Kooy, R. Frank; Isidor, Bertrand; Schwartz, Charles; Romano, Corrado; Sistermans, Erik A.; Amor, David J.; Andrieux, Joris; Girirajan, Santhosh

doi:10.1038/s41436-018-0266-3

Cited by 131 publications

(155 citation statements)

References 40 publications

(66 reference statements)

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“…We first compared the phenotypes of 288 individuals with de novo LGD variants and 81 individuals with pathogenic CNVs to 1,921 individuals without such variants obtained from the SSC cohort. Similar to previous autism studies that identified correlations between de novo variants and IQ scores 9–12 , we found that individuals with de novo LGD variants (IQ=77.7, p=0.031, two-tailed Mann-Whitney test) or pathogenic CNVs (IQ=76.3, p=0.002) had a significant decrease in IQ scores compared with individuals without such variants (IQ=82.3) ( Figure 1A ). However, no differences in autism severity, measured using SRS T-scores, were observed between groups of individuals with and without pathogenic variants (p=0.104 for LGD variants and 0.963 for CNVs) ( Figure 1A ).…”

supporting

confidence: 89%

Gene discoveries in autism are biased towards comorbidity with intellectual disability

Jensen

Smolen

Girirajan

2019

Preprint

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21Autism typically presents with a highly heterogeneous set of features, including frequent 22we found that individuals with de novo LGD variants (IQ=77.7, p=0.031, Whitney test) or pathogenic CNVs (IQ=76.3, p=0.002) had a significant decrease in IQ scores 65 compared with individuals without such variants (IQ=82.3) ( Figure 1A). However, no 66 differences in autism severity, measured using SRS T-scores, were observed between groups of 67 individuals with and without pathogenic variants (p=0.104 for LGD variants and 0.963 for 68 CNVs) ( Figure 1A). This suggests that pathogenic variants in general contribute to ID 69 independent of autism severity, although this could also be due to an ascertainment bias in the 70 SSC cohort towards individuals with severe autism. 71We further identified individuals carrying de novo LGD variants in 173 autism-associated 72 genes, defined as genes with recurrent de novo variants reported in multiple databases of 73 manifesting ID among individuals with autism (p=0.035, 95% confidence interval 1.03-2.26), 96 and pathogenic CNVs similarly conferred a 1.92-fold increased risk for co-occurrence of ID 97 among individuals with autism (p=0.099, 95% CI 0.88-4.18). We replicated these observations 98 by analyzing an additional combined cohort of 2,357 individuals from both the SSC and the 99 Autism Sequencing Collection 18 . Here, individuals with autism and ID had a significantly higher 100 rate (p=3.04×10 -6 , one-tailed Student's t-test) of de novo variants in genes intolerant to variation, 101as measured by probability of Loss-of-function Intolerant (pLI) score >0.9 (70/643, 10.8%), than 102 individuals manifesting autism but not ID (114/1747, 6.65%). We also found that only 3/397 BrainSpan Atlas 21 , using the Specific-Expression Analysis (SEA) online tool 22 . While autism 126 genes were enriched for specific expression in the cortex (p=3.13×10 -4 , Fisher's Exact test with 127Benjamini-Hochsberg correction) and cerebellum (p=0.020) during early fetal development 22 , 128 genes with de novo LGD variants in high-functioning autism individuals were not enriched for 129 any specific expression patterns in the developing brain (Figure 2B). Furthermore, mouse 130 models of genes identified in individuals with high-functioning autism, whose phenotypic data 131 were obtained from the Mouse Genome Informatics database 24 , were significantly less likely to 132 manifest nervous system (p=4.90×10 -3 , one-tailed Fisher's Exact test with Benjamini-Hochsberg 133 correction) and behavioral/neurological (p=0.037) phenotypes than mouse models of reported 223 224 5. Fischbach, G.D., and Lord, C. (2010). The Simons Simplex Collection: A Resource for 225

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supporting

confidence: 89%

Gene discoveries in autism are biased towards comorbidity with intellectual disability

Jensen

Smolen

Girirajan

2019

Preprint

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“…Together, these data offer independent support of the genetic complexity underlying phenotypes in the 16p11.2 locus and reinforce a likely oligogenic etiology with primary drivers and multiple modifiers governing the variance in associated traits [42,57,76,77].…”

Section: Discussionmentioning

confidence: 61%

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Männik

Arbogast

Lepamets

et al. 2019

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Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.

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“…In terms of neuropsychiatric disease, perhaps multiple genetic risk factors, in combination with different environmental exposures act together to impact the complex human brain, but with varying phenotypic consequences depending on the specific genetic/environmental combination. In fact, a recent study suggests that variation in genetic background in combination with defects in developmental susceptibility genes could explain phenotypic variability (Pizzo et al, 2018), and perhaps stress could also be added to this model. Underlying genetic differences, including defects in susceptibility genes, may only impact some neuronal responses to stress during certain critical periods, which may differ for each stress/genetic risk, adding further complexity and variability to relevant phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Stress-induced neuron remodeling reveals differential interplay between neurexin and environmental factors

2018

Preprint

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Neurexins are neuronal adhesion molecules important for synapse maturation, function, and plasticity. Neurexins have been genetically associated with neurodevelopmental disorders including autism spectrum disorders (ASDs) and schizophrenia, but can have variable penetrance and phenotypic severity. Heritability studies indicate that a significant percentage of risk for ASD and schizophrenia includes environmental factors, highlighting the poorly understood interplay between genetic and environmental factors in pathogenesis of these disorders. The singular C. elegans ortholog of human neurexins, nrx-1, controls experience-dependent morphologic remodeling of a GABAergic neuron in adult males. Here I show that this GABAergic neuron's morphology is altered in response to each of three environmental stressors (nutritional, heat, or genotoxic stress) applied during sexual maturation, but not during adulthood. Increased outgrowth of axon-like neurites following adolescent stress results from an altered morphologic plasticity that occurs upon entry into adulthood. Despite axonal remodeling being induced by each of the three stressors, only nutritional stress (starvation) impacts behavior and is dependent on neurexin/nrx-1. Heat or genotoxic stress during sexual maturation did not alter behavior despite inducing GABAergic neuron remodeling, and this remodeling was independent of neurexin/nrx-1. Remodeling induced by starvation stress was found be dependent on neuroligin/nlg-1, the canonical binding partner for neurexin/nrx-1, as well as the stress signaling transcription factors FOXO/daf-16 and HSF1/hsf-1, each of which was also found to have unique roles in remodeling induced by heat and UV stress. The differential molecular mechanisms underlying GABAergic neuron remodeling in response to different stressors, and the disparate effects of stressors on behavior, is a novel paradigm for understanding how genetics, environmental exposures, and plasticity may contribute to brain dysfunction in ASDs and schizophrenia.

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Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants

Abstract: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

Cited by 131 publications

References 40 publications

Gene discoveries in autism are biased towards comorbidity with intellectual disability

Gene discoveries in autism are biased towards comorbidity with intellectual disability

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Stress-induced neuron remodeling reveals differential interplay between neurexin and environmental factors

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