ArticleAmerican journal of human genetics2012
Scan-statistic approach identifies clusters of rare disease variants in LRP2, a gene linked and associated with autism spectrum disorders, in three datasets.
Article in American journal of human genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed.
- A De NovoInternational journal of molecular sciences · 2026Article
- LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.Journal of neuropathology and experimental neurology · 2023Article
- Recent advances and challenges of rare variant association analysis in the biobank sequencing era.Frontiers in genetics · 2022Review
- Contribution of Rare and Low-Frequency Variants to Multiple Sclerosis Susceptibility in the Italian Continental Population.Frontiers in genetics · 2021Article
- PSCAN: Spatial scan tests guided by protein structures improve complex disease gene discovery and signal variant detection.Genome biology · 2020Article
- VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction.EBioMedicine · 2020Article
- The MUC6/AP2A2 Locus and Its Relevance to Alzheimer's Disease: A Review.Journal of neuropathology and experimental neurology · 2020Review
- Quantitative phenotype scan statistic (QPSS) reveals rare variant associations with Alzheimer's disease endophenotypes.BMC medical genetics · 2020Article
- Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypesJournal of psychiatry & neuroscience : JPN · 2019Article
- Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome.International journal of molecular sciences · 2019Review
- Article
- Identifying individual risk rare variants using protein structure guided local tests (POINT).PLoS computational biology · 2019Article
- GxGrare: gene-gene interaction analysis method for rare variants from high-throughput sequencing data.BMC systems biology · 2018Article
- The impact of a fine-scale population stratification on rare variant association test results.PloS one · 2018Article
- Spatial statistical tools for genome-wide mutation cluster detection under a microarray probe sampling system.PloS one · 2018Article
- Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome.Translational psychiatry · 2017Article
- Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians.European journal of human genetics : EJHG · 2017Article
- DoEstRare: A statistical test to identify local enrichments in rare genomic variants associated with disease.PloS one · 2017Article
- Bayesian inference on quasi-sparse count data.Biometrika · 2016Article
- Block-based association tests for rare variants using Kullback-Leibler divergence.Journal of human genetics · 2016Article
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Abstract
Cluster-detection approaches, commonly used in epidemiology and astronomy, can be applied in the context of genetic sequence data for the identification of genetic regions significantly enriched with rare disease-risk variants (DRVs). Unlike existing association tests for sequence data, the goal of cluster-detection methods is to localize significant disease mutation clusters within a gene or region of interest. Here, we focus on a chromosome 2q replicated linkage region that is associated with autism spectrum disorder (ASD) and that has been sequenced in three independent datasets. We found that variants in one gene, LRP2, residing on 2q are associated with ASD in two datasets (the combined variable-threshold-test p value is 1.2 × 10(-5)). Using a cluster-detection method, we show that in the discovery and replication datasets, variants associated with ASD cluster preponderantly in 25 kb windows (adjusted p values are p(1) = 0.003 and p(2) = 0.002), and the two windows are highly overlapping. Furthermore, for the third dataset, a 25 kb region similar to those in the other two datasets shows significant evidence of enrichment of rare DRVs. The region implicated by all three studies is involved in ligand binding, suggesting that subtle alterations in either LRP2 expression or LRP2 primary sequence modulate the uptake of LRP2 ligands. BMP4 is a ligand of particular interest given its role in forebrain development, and modest changes in BMP4 binding, which binds to LRP2 near the mutation cluster, might subtly affect development and could lead to autism-associated phenotypes.
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