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. 2019 Sep 1;44(5):350-359.
doi: 10.1503/jpn.180184.

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

Bàrbara Torrico  1 , Alex D. Shaw  1 , Roberto Mosca  1 , Norma Vivó-Luque  1 , Amaia Hervás  1 , Noèlia Fernàndez-Castillo  1 , Patrick Aloy  1 , Mònica Bayés  1 , Janice M. Fullerton  1 , Bru Cormand  1 , Claudio Toma  1
Affiliations

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

Bàrbara Torrico et al. J Psychiatry Neurosci. .

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 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.

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Conflict of interest statement

None declared.

Figures

Fig. 1
Fig. 1
Effect of the identified de novo change on LRP1 splicing. (A) Schematic structure of the LRP1 gene (NM_002332), with exons 28 to 30 amplified below. The mutation site is indicated by a triangle (c.5205–2A>G). (B) Polymerase chain reaction (PCR) analysis of LRP1 complementary DNA from lymphocytes visualized on polyacrylamide gel. For the wild-type (WT) transcript, the PCR amplicon of 360 bp included a fragment of exon 28, the entire exon 29 and a fragment of exon 30, whereas the mutated transcript (Mut) generated a smaller fragment (132 bp) lacking exon 29 (76 amino acids), which generates an in-frame transcript. The 2 transcripts spanning exon 28 to 30 are represented by the sequenced band of the mutated allele. (C) Schematic representation of LRP1 domains with the β-propellers as hexagons. The region encoded by exon 29 in β-propeller 4 is in red. (D) Cartoon model for the LRP1 domain β-propellers 3 and 4 obtained from the template of the β-propeller domains 1 and 2 of LRP6 (PDB ID 3s94). The skipping of exon 29 led to the removal of the first 2 blades of 6 from β-propeller 4.
Fig. 2
Fig. 2
The boxplots show the cytokine expression in immortalized lymphocyte cell lines from the patient (Mut) and a control (wild-type; WT) with (+) or without (−) treatment of lipopolysaccharide (6 h at 1 mg/mL). The mRNA quantifications of (A) interleukin-10 (IL-10), (B) interleukin-6 (IL-6) and (C) tumour necrosis factor α (TNFα) were normalized using ACTB as an endogenous reference. *p < 0.05; **p < 0.0005.
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