Faculty Bibliography
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523
Association between microdeletion and microduplication at 16p11.2 and autism
BACKGROUND: Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. METHODS: As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. RESULTS: Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. CONCLUSIONS: We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations.
PMID: 18184952
ISSN: 1533-4406
CID: 2747712
Allele-specific expression in the germline of patients with familial pancreatic cancer: an unbiased approach to cancer gene discovery
Physiologic allele-specific expression (ASE) in germline tissues occurs during random X-chromosome inactivation and in genomic imprinting, wherein the two alleles of a gene in a heterozygous individual are not expressed equally. Recent studies have confirmed the existence of ASE in apparently non-imprinted autosomal genes; however, the extent of ASE in the human genome is unknown. We explored ASE in lymphoblastoid cell lines of 145 individuals using an oligonucleotide array based assay. ASE of autosomal genes was found to be a very common phenomenon in approximately 20% of heterozygotes at 78% of SNPs at 84% of the genes examined. Comparison of 100 affected individuals from familial pancreatic cancer kindreds and 45 controls revealed three types of changes in the germline: (a) loss of ASE, (b) gain of ASE, and, (c) rare instances of "extreme" (near monoallelic) ASE. The latter changes identified heterozygous deleterious mutations in a subset of these genes. Consequently, an ASE assay efficiently identifies candidate disease genes with altered germline expression properties as compared to controls, and provides insights into mechanisms that confer an inherited disease risk for pancreatic cancer.
PMCID:4104667
PMID: 18059179
ISSN: 1555-8576
CID: 2747732
Hirschsprung disease, associated syndromes and genetics: a review
Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.
PMID: 17965226
ISSN: 1468-6244
CID: 3975222
A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism
Autism is a childhood neuropsychiatric disorder that, despite exhibiting high heritability, has largely eluded efforts to identify specific genetic variants underlying its etiology. We performed a two-stage genetic study in which genome-wide linkage and family-based association mapping was followed up by association and replication studies in an independent sample. We identified a common polymorphism in contactin-associated protein-like 2 (CNTNAP2), a member of the neurexin superfamily, that is significantly associated with autism susceptibility. Importantly, the genetic variant displays a parent-of-origin and gender effect recapitulating the inheritance of autism.
PMCID:2253968
PMID: 18179894
ISSN: 1537-6605
CID: 2747722
RET, Hirschsprung disease and multiple endocrine neoplasia type 2
Oxford ; New York : Oxford University Press, 2008
pp. 421-432
ISBN: 0195306910
CID: 3987712
A second generation human haplotype map of over 3.1 million SNPs
We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.
PMCID:2689609
PMID: 17943122
ISSN: 1476-4687
CID: 2747752
Genome-wide detection and characterization of positive selection in human populations
With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.
PMCID:2687721
PMID: 17943131
ISSN: 1476-4687
CID: 2747742
Long QT syndrome genes modulate the effect of NOS1AP haplotypes on cardiac repolarization [Meeting Abstract]
ISI:000250394303066
ISSN: 0009-7322
CID: 2748402
An ancestral variant of Secretogranin II confers regulation by PHOX2 transcription factors and association with hypertension
Granins regulate secretory vesicle formation in neuroendocrine cells and granin-derived peptides are co-released with neurotransmitters as modulatory signals at sympathetic sites. We report evidence for association between a regulatory polymorphism in Secretogranin II (SCG2) and hypertension in African-American subjects. The minor allele is ancestral in the human lineage and is associated with disease risk in two case-control studies and with elevated blood pressure in a separate familial study. Mechanistically, the ancestral allele acts as a transcriptional enhancer in cells that express endogenous Scg2, whereas the derived allele does not. ARIX (PHOX2A) and PHOX2B are identified as potential transactivating factors by oligonucleotide affinity chromatography and mass spectrometry and confirmed by chromatin immunoprecipitation. Each of these transcription factors preferentially binds the risk allele, both in vitro and in vivo. Population genetic considerations suggest positive selection of the protective allele within the human lineage. These results identify a common regulatory variation in SCG2 and implicate granin gene expression in the control of human blood pressure and susceptibility to hypertension.
PMCID:2695823
PMID: 17584765
ISSN: 0964-6906
CID: 2747772
Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits
The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7)), hip circumference (p = 3.4 x 10(-8)), and weight (p = 9.1 x 10(-7)). In Sardinia, homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6)). Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common "G" allele. In summary, we have completed a whole genome-association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.
PMCID:1934391
PMID: 17658951
ISSN: 1553-7404
CID: 2747762
