Polymorphisms in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in populations of European ancestry

In order to gain a better understanding of how the genetic variation within these four gene regions may influence susceptibility to ASDs, a family-based association study was undertaken in 661 families of European ancestry selected from four different ASD cohorts. In addition, a case-control study was undertaken across the four LRR genes, using logistic regression in probands with ASD of each population against 295 ECACC controls.Significant results were found for LRRN3 and LRRTM3 (P < 0.005), using both single locus and haplotype approaches. These results were further supported by a case-control analysis, which also highlighted additional SNPs in LRRTM3.Overall, our findings implicate the neuronal leucine-rich genes LRRN3 and LRRTM3 in ASD susceptibility.Autism is a genetically complex neurodevelopmental disorder, characterized by impairments in reciprocal social interaction and communication, along with restricted and stereotyped patterns of interests and behaviours [1]. It is an extremely heterogeneous and highly heritable condition, affecting predominantly males (with an average sex ratio of 4:1), and with an onset before 3 years of age [2,3]. Autism spectrum disorders (ASDs) refers to a broad definition of autism, including classical and atypical autism, Asperger syndrome and pervasive developmental disorder not otherwise specified [4]. The aetiology of ASD is not fully understood and the causal variants and their modes of transmission remain elusive.Leucine-rich repeats (LRRs) are common protein-protein interaction motifs and are typically 20-29 amino acids in length [5]. LRR proteins are highly expressed in the nervous system and are involved in numerous biological functions, including nervous system development [5-10]. Mutations in LRR genes have been associated with different diseases, such as hereditary lateral temporal epilepsy [11] and Parkinson disease [12]. Furthermore, a recent study suggested that LRR variants could possibly be involved in ASD suscep