4.5 Article

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

Journal

JOURNAL OF PSYCHIATRY & NEUROSCIENCE
Volume 44, Issue 5, Pages 350-359

Publisher

CMA-CANADIAN MEDICAL ASSOC
DOI: 10.1503/jpn.180184

Keywords

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Funding

  1. European Union [PIEF-GA-2009-254930]
  2. AGAUR (Generalitat de Catalunya)
  3. Fundacio La Marato de TV3 [092010]
  4. AGAUR [2017SGR738]
  5. Spanish Ministerio de Economia y Competitividad [SAF2015-68341-R, BIO2013-48222-R, BIO2016-77038-R]
  6. Australian National Medical and Health Research Council (NHMRC) [1037196, 1063960, 1066177]
  7. European Union H2020 Program (H2020/2014-2020) [667302, 643051]
  8. European Research Council [SysPharmAD: 614944]
  9. Janette Mary O'Neil Research Fellowship
  10. Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)
  11. Fundacion Alicia Koplowitz

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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 beta-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 x E-07) and in a meta-analysis across 7 psychiatric disorders (p = 2.3 x E-03); and the burden of ultra-rare pathogenic variants has been shown to be higher in autism-spectrum disorder (p = 1.2 x 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.

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