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Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes

ABSTRACT: Background:Previous research has implicated de novo and inherited truncating mutations in autism-spectrum disorder. We aim to investigate whether the load of inherited truncating mutations contributes similarly to high-functioning autism, and to characterize genes that harbour de novo variants in high-functioning autism. Methods:We performed whole-exome sequencing in 20 high-functioning autism families (average IQ = 100). Results:We observed no difference in the number of transmitted versus nontransmitted truncating alleles for high-functioning autism (117 v. 130, p = 0.78). Transmitted truncating and de novo variants in high-functioning autism were not enriched in gene ontology (GO) or Kyoto Encyclopedia of Genes and Genomes (KEGG) categories, or in autism-related gene sets. However, in a patient with high-functioning autism we identified a de novo variant in a canonical splice site of LRP1, a postsynaptic density gene that is a target for fragile X mental retardation protein (FRMP). This de novo variant leads to in-frame skipping of exon 29, removing 2 of 6 blades of the ?-propeller domain 4 of LRP1, with putative functional consequences. Large data sets implicate LRP1 across a number of psychiatric disorders: de novo variants are associated with autism-spectrum disorder (p = 0.039) and schizophrenia (p = 0.008) from combined sequencing projects; common variants using genome-wide association study data sets from the Psychiatric Genomics Consortium show gene-based association in schizophrenia (p = 6.6 × E?07) and in a meta-analysis across 7 psychiatric disorders (p = 2.3 × E?03); and the burden of ultra-rare pathogenic variants has been shown to be higher in autism-spectrum disorder (p = 1.2 × E?05), using whole-exome sequencing from 6135 patients with schizophrenia, 1778 patients with autism-spectrum disorder and 7875 controls. Limitations:We had a limited sample of patients with high-functioning autism, related to difficulty in recruiting probands with high cognitive performance and no family history of psychiatric disorders. Conclusion:Previous studies and ours suggest an effect of truncating mutations restricted to severe autism-spectrum disorder phenotypes that are associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.

SUBMITTER: Torrico B

PROVIDER: S-EPMC6710089 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes

Torrico Bàrbara B Shaw Alex D. AD Mosca Roberto R Vivó-Luque Norma N Hervás Amaia A Fernàndez-Castillo Noèlia N Aloy Patrick P Bayés Mònica M Fullerton Janice M. JM Cormand Bru B Toma Claudio C

Journal of psychiatry & neuroscience : JPN 20190901 5

<h4>Background</h4>Previous research has implicated de novo and inherited truncating mutations in autism-spectrum disorder. We aim to investigate whether the load of inherited truncating mutations contributes similarly to high-functioning autism, and to characterize genes that harbour de novo variants in high-functioning autism.<h4>Methods</h4>We performed whole-exome sequencing in 20 high-functioning autism families (average IQ = 100).<h4>Results</h4>We observed no difference in the number of t ...[more]

PMID: 31094488

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Project description:BACKGROUND: The objective of this study was to examine differences in episodic memory retrieval between individuals with autism spectrum disorder (ASD) and typically developing (TD) individuals. Previous studies have shown that personality similarities between readers and characters facilitated reading comprehension. Highly extraverted participants read stories featuring extraverted protagonists more easily and judged the outcomes of such stories more rapidly than did less extraverted participants. Similarly, highly neurotic participants judged the outcomes of stories with neurotic protagonists more rapidly than did participants with low levels of neuroticism. However, the impact of the similarity effect on memory retrieval remains unclear. This study tested our 'similarity hypothesis', namely that memory retrieval is enhanced when readers with ASD and TD readers read stories featuring protagonists with ASD and with characteristics associated with TD individuals, respectively. METHODS: Eighteen Japanese individuals (one female) with high-functioning ASD (aged 17 to 40 years) and 17 age- and intelligence quotient (IQ)-matched Japanese (one female) TD participants (aged 22 to 40 years) read 24 stories; 12 stories featured protagonists with ASD characteristics, and the other 12 featured TD protagonists. Participants read a single sentence at a time and pressed a spacebar to advance to the next sentence. After reading all 24 stories, they were asked to complete a recognition task about the target sentence in each story. RESULTS: To investigate episodic memory in ASD, we analyzed encoding based on the reading times for and readability of the stories and retrieval processes based on the accuracy of and response times for sentence recognition. Although the results showed no differences between ASD and TD groups in encoding processes, they did reveal inter-group differences in memory retrieval. Although individuals with ASD demonstrated the same level of accuracy as did TD individuals, their patterns of memory retrieval differed with respect to response times. CONCLUSIONS: Individuals with ASD more effectively retrieved ASD-congruent than ASD-incongruent sentences, and TD individuals retrieved stories with TD more effectively than stories with ASD protagonists. Thus, similarity between reader and story character had different effects on memory retrieval in the ASD and TD groups.

Dataset Information

Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes

Publications

Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes

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