There is strength in numbers. Large sample populations are necessary in gene association studies of complex disorders, like autism spectrum disorders (ASDs), because multiple genes may contribute, and distinct genetic abnormalities may cause different types of ASD. The Autism Genome Project Consortium genotyped more than 10,000 single-nucleotide polymorphisms for nearly 8000 people in over 1400 families with 2 or more members affected by ASD. They report new genetic regions associated with ASD in a recent article in Nature Genetics.
ASDs are neurodevelopmental disorders that impair communication and social interaction and cause stereotyped patterns of behavior. Males are affected by ASD four times as frequently as females. Previous genome-wide linkage scans associated chromosomal regions 2q, 7q and 17q with ASD. Other studies associated chromosomal duplications in chromosomal region 15q with ASD, suggesting that chromosomal abnormalities may be important in ASD.
The Autism Genome Project Consortium looked for chromosomal copy number abnormalities associated with ASD. They converted the expression intensity of single-nucleotide polymorphisms to discrete chromosomal copy numbers and identified 254 copy number variants (CNV) associated with ASD. The affected children in 10 families had de novo CNVs (possessed by neither parent). For example, in one family, two affected sisters carried de novo deletions in chromosomal region 2p16. A total of 18 CNVs found in unrelated people with ASD localized to genetic regions already associated with ASD, and 47 CNVs recurred in multiple families. For example, affected individuals in three families showed duplications of chromsomal region 1q21, which is implicated in mental retardation.
Linkage analyses associated chromosomal region 11p12-p13 with ASD. Linkage analysis of the entire population, regardless of differences in symptom severity in ASD-affected individuals, associated this chromosomal region with ASD. Linkage analysis of small subsets of the population, including the subset of families containing ASD-affected females and the subset of families lacking identified CNVs, also associated ASD with abnormalities in 11p12-p13.
Which genes reside in ASD-associated regions? The high-affinity glutamate transporters SLC1A1 and SLC1A2 localize near peak linkage regions. Genetic region 2p16 contains neurexin 1 (NRXN1). Neurexins are important in the differentiation of dendrite postsynaptic densitites. Neuroligins, previously implicated in ASD, are important in the maturation of presynaptic sites in glutamatergic axons. Therefore, disruption of the glutamatergic system during development may contribute to ASD.