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

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

J Psychiatry Neurosci 2019;44(5):350-359 | PDF | Appendix

Bàrbara Torrico, PhD; Alex D. Shaw, PhD; Roberto Mosca, PhD; Norma Vivó-Luque, BSc; Amaia Hervás, MD; Noèlia Fernàndez-Castillo, PhD; Patrick Aloy, PhD; Mònica Bayés, PhD; Janice M. Fullerton, PhD; Bru Cormand, PhD*; Claudio Toma, PhD*

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 β-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.

*These authors contributed equally to this work.

Submitted Oct. 10, 2018; Revised Jan. 21, 2019; Revised Jan. 26, 2019; Accepted Feb. 8, 2019; Published online on May 16

Acknowledgements: The authors are grateful to all patients and their families for their participation, and thank all clinical collaborators who contributed to the diagnosis of probands. C. Toma was supported by the European Union (Marie Curie, PIEF-GA-2009-254930) and B. Torrico by AGAUR (Generalitat de Catalunya). Financial support was received from Fundació La Marató de TV3 (092010), Fundación Alicia Koplowitz, AGAUR (2017SGR738), the Spanish Ministerio de Economía y Competitividad (SAF2015-68341-R) and the Australian National Medical and Health Research Council (NHMRC) Project Grant 1063960 and 1066177, and Program Grant 1037196. The research leading to these results also received funding from the European Union H2020 Program (H2020/2014-2020) under grant agreements 667302 (CoCA) and 643051 (MiND). P. Aloy acknowledges the support of the Spanish Ministerio de Economía y Competitividad (BIO2013-48222-R; BIO2016-77038-R) and the European Research Council (SysPharmAD: 614944). J.M. Fullerton was supported by the Janette Mary O’Neil Research Fellowship. N. Fernàndez-Castillo was supported by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). Exome sequencing services were provided by the National Centre for Genomic Analysis (CNAG). The authors also thank the CIBERER Biobank (, Rafael Valdés-Mas and Xose S. Puente from the University of Oviedo (Spain) for support in bioinformatics analyses, and Barbara Toson (NeuRA) for support in statistical analyses.

Affiliations: From the Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Spain (Torrico, Vivó-Luque, Fernàndez-Castillo, Cormand, Toma); the Institute of Biomedicine, University of Barcelona, Barcelona, Spain (Torrico, Fernàndez-Castillo, Cormand, Toma); the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain (Torrico, Fernàndez-Castillo, Cormand, Toma); the Institut de Recerca Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain (Torrico, Fernàndez-Castillo, Cormand); the Neuroscience Research Australia, Sydney, NSW, Australia (Shaw, Fullerton, Toma); the School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia (Shaw, Fullerton, Toma); the Institute for Research in Biomedicine (IRB Barcelona) and the Barcelona Institute of Science and Technology, Barcelona, Spain (Mosca, Aloy); the Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Spain (Hervás); the Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (Aloy); and the Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain (Bayés).

Competing interests: None declared.

Contributors: B. Torrico, M. Bayés, B. Cormand and C. Toma designed the study. B. Torrico and C. Toma acquired and analyzed the data, which A. Shaw, R. Mosca, N. Vivó-Luque, A. Hervás, N. Fernàndez-Castillo, P. Aloy, J. Fullerton and B. Cormand also analyzed. C. Toma wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.180184

Correspondence to: B. Cormand, Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain,; C. Toma, Neuroscience Research Australia, Margarete Ainsworth Building, Barker Street, Randwick NSW 2031, Sydney, Australia,