Summary Given prior evidence for the contribution of rare copy number variations (CNVs) to autism spectrum disorders (ASD), we studied these events in 4,457 individuals from 1,174 simplex families, composed of parents, a proband and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, featuring a highly social personality. We identify rare recurrent de novo CNVs at five additional regions including two novel ASD loci, 16p13.2 (including the genes USP7 and C16orf72) and Cadherin13, and implement a rigorous new approach to evaluating the statistical significance of these observations. Overall, we find large de novo CNVs carry substantial risk (OR=3.55; CI =2.16-7.46, p=6.9 × 10−6); estimate the presence of 130-234 distinct ASD-related CNV intervals across the genome; and, based on data from multiple studies, present compelling evidence for the association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin1.

Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNPs) in the coding region of the mu opioid receptor gene. The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study population. Significant differences in allele distribution were observed among ethnic groups studied. The variant receptor resulting from the A118G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds ␤-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic form of the receptor. Furthermore, ␤-endorphin is approximately three times more potent at the A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels. These results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.The mu opioid receptor is the primary site of action of several of the endogenous opioid peptides including ␤-endorphin, Met-enkephalin-Arg-Phe, and the recently identified endomorphins (1). This receptor is also the major target for clinically important opioid analgesic agents including morphine, methadone, fentanyl, and related drugs (2, 3). Activation of this receptor has diverse physiological effects (4, 5). Furthermore, it is the major molecular site of action for heroin (6, 7). Rapid activation of the mu opioid receptor, such as that which occurs in the setting of drug abuse, results in a euphoric effect, thus conferring the reinforcing or rewarding effects of the drug, contributing to the development of addiction. Clinical observations have suggested that individuals have varied sensitivity to opioids, suggesting potential variability in the receptor protein and gene. Naturally occurring polymorphisms are well known to exist in human genes; some have been shown to produce profound effects on the function of the corresponding proteins. Molecular cloning of the mu opioid receptor (8-11) has made it possible to determine potential sequence polymorphism, as shown by two recent studies (12, 13). The mu opioid receptor is a member of the G protein-coupled receptor family (8,14). There are a number of well documented cases where natural...

This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.