title: Converging evidence for an association of ATP2B2 allelic variants with autism in male subjects.
abstract: BACKGROUND
  Autism is a severe developmental disorder, with strong genetic underpinnings. Previous genome-wide scans unveiled a linkage region spanning 3.5 Mb, located on human chromosome 3p25. This region encompasses the ATP2B2 gene, encoding the plasma membrane calcium-transporting ATPase 2 (PMCA2), which extrudes calcium (Ca2+) from the cytosol into the extracellular space. Multiple lines of evidence support excessive intracellular Ca2+ signaling in autism spectrum disorder (ASD), making ATP2B2 an attractive candidate gene.
  
  
  METHODS
  We performed a family-based association study in an exploratory sample of 277 autism genetic resource exchange families and in a replication sample including 406 families primarily recruited in Italy.
  
  
  RESULTS
  Several markers were significantly associated with ASD in the exploratory sample, and the same risk alleles at single nucleotide polymorphisms rs3774180, rs2278556, and rs241509 were found associated with ASD in the replication sample after correction for multiple testing. In both samples, the association was present in male subjects only. Markers associated with autism are all comprised within a single block of strong linkage disequilibrium spanning several exons, and the "risk" allele seems to follow a recessive mode of transmission.
  
  
  CONCLUSIONS
  These results provide converging evidence for an association between ATP2B2 gene variants and autism in male subjects, spurring interest into the identification of functional variants, most likely involved in the homeostasis of Ca2+ signaling. Additional support comes from a recent genome-wide association study by the Autism Genome Project, which highlights the same linkage disequilibrium region of the gene.
authors.affiliation: Integragen SA, CEA-Genomics Institute, Évry, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Carayol
authors.forename: Roberto
authors.initials: R
authors.lastname: Sacco
authors.forename: Frédéric
authors.initials: F
authors.lastname: Tores
authors.forename: Francis
authors.initials: F
authors.lastname: Rousseau
authors.forename: Patricia
authors.initials: P
authors.lastname: Lewin
authors.forename: Jorg
authors.initials: J
authors.lastname: Hager
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Persico
mesh_terms: D000465:Algorithms; D000483:Alleles; D001321:Autistic Disorder / Q000235:genetics*; D004261:DNA Replication; D005190:Family; D005260:Female; D005808:Genes, Recessive; D005819:Genetic Markers; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007361:Intelligence Tests; D007558:Italy; D015810:Linkage Disequilibrium; D008297:Male; D008957:Models, Genetic; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales
chemical_list: D005819:Genetic Markers; D053499:Plasma Membrane Calcium-Transporting ATPases; C506958:ATP2B2 protein, human