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Neil Risch

Publications and source records attributed to Neil Risch.

At least 37 records · Page 2Linked to original sources
PubMed2004

Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population.

Glycogen storage disease type Ia (GSDIa) is a severe autosomal recessive disorder caused by deficiency of the enzyme D-glucose-6-phosphatase (G6Pase). While numerous mutations have been found in cosmopolitan European populations, Ashkenazi Jewish (AJ) patients appear to primarily carry the R83C mutation, but possibly also the Q347X mutation found generally in Caucasians. To determine the frequency for both these mutations in the AJ population, we tested 20,719 AJ subjects for the R83C mutation and 4,290 subjects for the Q347X mutation. We also evaluated the mutation status of 30 AJ GSDIa affected subjects. From the carrier screening, we found 290 subjects with R83C, for a carrier frequency for this mutation of 1.4%. This carrier frequency translates into a predicted disease prevalence of 1 in 20,000, five times higher than for the general Caucasian population, confirming a founder effect and elevated frequency of GSDIa in the AJ population. We observed no carriers of the Q347X mutation. Among the 30 GSDIa affected AJ subjects, all were homozygous for R83C. These results indicate that R83C is the only prevalent mutation for GSDIa in the Ashkenazi population.

Founder Effect↗
PubMed2004

Parent-of-origin effect in multiple sclerosis: observations in half-siblings.

Multiple sclerosis is a complex trait in which occurrence rates in offspring are 20-50-fold greater than in the general population. Parent-of-origin effects have been difficult to screen for, since most cases are sporadic. We have compared recurrence risks in half-siblings with respect to their parent in common. Of the 1567 index cases with half-siblings in multiple sclerosis clinics across Canada, we recorded 3436 half-siblings and 2706 full-siblings. Age-adjusted full-sibling risk was 3.11%. By contrast, half-sibling risk in the same families was significantly lower at 1.89% (chi2 test, p=0.006), but higher than expected if familial risk was simply polygenic. For maternal half-siblings, the risk was 2.35% (34 affected siblings of 1859), and 1.31% for paternal half-siblings (15 of 1577), (p=0.048). The difference in risk suggests a maternal parent-of-origin effect in multiple sclerosis susceptibility.

Female↗
PubMed2004

An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group.

Multiple sclerosis (MS) is a complex trait with a sibling relative risk (lambda(sibs)) between 18 and 36. We report a multistage genome scan of 552 sibling pairs from 442 families, the largest MS family sample assessed for linkage. The first stage consisted of a genome scan for linkage with 498 microsatellite markers at an average spacing of 7 cM in 219 sibling pairs. The second stage involved further genotyping of markers from positive regions in an independent sample of 333 affected sibling pairs. The global distribution of allele sharing for all markers showed a shift towards greater sharing within the affected sibling pair group but not in the discordant sibling pair group. This shift indicates that the number of contributing genetic factors is likely to be moderate to large. Only markers at chromosome 6p showed significant evidence for linkage (MLOD=4.40), while other regions were only suggestive (1p, 2q, 5p, 9q, 11p, 12q, 18p, 18q and 21q) with MLODs greater than 1.0. The replication analysis involving all 552 affected sibling pairs confirmed suggestive evidence for five locations, namely, 2q27 (MLOD=2.27), 5p15 (MLOD=2.09), 18p11 (MLOD=1.68), 9q21 (MLOD=1.58) and 1p31 (MLOD=1.33). Suggestive linkage evidence for a previously reported location on chromosome 17q (MLOD=1.67) and a prior association with marker D17S789 was replicated. We showed that the overall excess allele sharing we observed for the entire sample was due to increased allele sharing within the DRB1*15 negative subgroup alone. This observation is most consistent with a model of genetic heterogeneity between HLA and other genetic loci. These findings offer guidance for future genetic studies including dense SNP linkage disequilibrium analysis.

Canada↗
PubMed2004

Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.

Autism is a pervasive neurodevelopmental disorder characterized by deficits in language development and social interaction, as well as stereotypical, repetitive behaviors. The etiology of autism is largely unknown. Family and twin studies have provided compelling evidence for a strong genetic component in most idiopathic cases. Several recent candidate gene studies have suggested that alleles of WNT2 and the reelin gene (RELN), two genes involved in distinct aspects of neurodevelopment, confer greater susceptibility to autism. We screened WNT2 for DNA polymorphisms by sequencing all exons and adjacent intronic regions in 24 autistic patients, and identified not only the WNT2 variants reported previously (two common single-nucleotide polymorphisms (SNPs) in the 5' upstream region and the 3' untranslated region (UTR), respectively), but also two new SNPs in its 3' UTR. We genotyped all four WNT2 polymorphisms and a polymorphic trinucleotide repeat in the 5' UTR of RELN in 107 families with multiple autistic children, and evaluated evidence for association between these variants and autism by the transmission disequilibrium test (TDT). Our results revealed no deviation from the null hypothesis of no association. Our interpretation of these findings is that it is unlikely that DNA variations in RELN and WNT2 play a significant role in the genetic predisposition to autism.

5' Untranslated Regions↗
PubMed2004

Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and Sephardi/Oriental Jewish families.

Crohn disease (CD), an inflammatory bowel disease, is a multifactorial trait with the highest frequency in Ashkenazi Jewish (AJ) individuals of Central European origin. Recently, three common predisposing CARD15 mutations (R702W, G908R, and 1007fs) and a polymorphism (P268S) were identified. To determine whether CARD15 mutations account for the higher prevalence of CD in AJ individuals, the haplotypes and allele frequencies of the common mutations and variants were assessed in 219 members of 50 AJ and 53 members of 10 Sephardi/Oriental Jewish (SOJ) multiplex families with CD, in 36 AJ patients with sporadic CD, and in 246 AJ and 82 SOJ controls. A higher frequency of CARD15 mutations was found in AJ patients from multiplex families with CD from Central (44.0%) versus Eastern (24.0%) Europe, especially for G908R and 1007fs, and in SOJ patients (34.5%) compared with AJ (10.1%) or SOJ (5.4%) controls. Contrary to expectation, the frequency of the common mutations was slightly lower in AJ patients with CD (30.1%) than in SOJ patients with CD (34.5%). The 702W allele was associated with both the P268 and 268S alleles. CARD15 mutation frequencies were greater in affected sib pairs than in sporadic CD cases but actually decreased in families with three or more affected sibs, raising the possibility of genetic heterogeneity. Similarly, our linkage evidence on chromosome 16 was diminished in the families with three or more affected sibs compared with sib pairs. Screening the CARD15 gene for rare variants revealed five novel changes (D113N, D357A, I363F, L550V, and N852S) of which N852S occurred only in AJ individuals and may be disease predisposing. Also, there was no evidence for increased risk associated with the recently described IVS(+158) single-nucleotide polymorphism. Although the AJ controls appear to have a higher frequency of CARD15 mutations than the SOJ controls, it is unlikely that this difference fully explains the excess frequency of CD in the AJ population.

Alleles↗
PubMed2004

Assessing genetic contributions to phenotypic differences among 'racial' and 'ethnic' groups.

Descriptions of human genetic variation given thirty years ago have held up well, considering the substantial accrual of DNA sequence data in the interim. Most importantly, estimates of between-group genetic variation have remained relatively low. Despite the low average level of between-group variation, clusters recently inferred from multilocus genetic data coincide closely with groups defined by self-identified race or continental ancestry. This correspondence implies that genetic factors might contribute to unexplained between-group phenotypic variation. Current understanding of the contribution of genes to variation in most complex traits is limited, however. Under these circumstances, assumptions about genetic contributions to group differences are unfounded. In the absence of detailed understanding, 'racial' and 'ethnic' categories will remain useful in biomedical research. Further, we suggest approaches and guidelines for assessing the contribution of genetic factors to between-group phenotypic differences, including studies of candidate genes and analyses of recently admixed populations.

DNA↗
PubMed2003

Genomic priorities and public health.

Given the continuing difficulty of identifying genes for complex disorders in a robust, replicable manner, and the extensive resources devoted to this effort, it is becoming increasingly important to analyze the relative benefits of genomics research for public health applications and for the understanding of disease pathogenesis. To establish priorities for genetics research, we review and evaluate several characteristics of selected exemplary complex diseases, including phenotypic accuracy, knowledge of specific and nonspecific genetic and environmental risk factors, and population prevalence and impact. We propose that complex diseases with the strongest evidence for genetic etiology, limited ability to modify exposure or risk factors, and high public health impact should have the highest priority for genetics research.

Environment↗
PubMed2003

Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome.

Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM 604168) is an autosomal recessive developmental disorder that occurs in an endogamous group of Vlax Roma (Gypsies; refs. 1-3). We previously localized the gene associated with CCFDN to 18qter, where a conserved haplotype suggested a single founder mutation. In this study, we used recombination mapping to refine the gene position to a 155-kb critical interval. During haplotype analysis, we found that the non-transmitted chromosomes of some unaffected parents carried the conserved haplotype associated with the disease. Assuming such parents to be completely homozygous across the critical interval except with respect to the disease-causing mutation, we developed a new 'not quite identical by descent' (NQIBD) approach, which allowed us to identify the mutation causing the disease by sequencing DNA from a single unaffected homozygous parent. We show that CCFDN is caused by a single-nucleotide substitution in an antisense Alu element in intron 6 of CTDP1 (encoding the protein phosphatase FCP1, an essential component of the eukaryotic transcription machinery), resulting in a rare mechanism of aberrant splicing and an Alu insertion in the processed mRNA. CCFDN thus joins the group of 'transcription syndromes' and is the first 'purely' transcriptional defect identified that affects polymerase II-mediated gene expression.

Amino Acid Sequence↗
PubMed2003

Natural variation in human membrane transporter genes reveals evolutionary and functional constraints.

Membrane transporters maintain cellular and organismal homeostasis by importing nutrients and exporting toxic compounds. Transporters also play a crucial role in drug response, serving as drug targets and setting drug levels. As part of a pharmacogenetics project, we screened exons and flanking intronic regions for variation in a set of 24 membrane transporter genes (96 kb; 57% coding) in 247 DNA samples from ethnically diverse populations. We identified 680 single nucleotide polymorphisms (SNPs), of which 175 were synonymous and 155 caused amino acid changes, and 29 small insertions and deletions. Amino acid diversity (pi(NS)) in transmembrane domains (TMDs) was significantly lower than in loop domains, suggesting that TMDs have special functional constraints. This difference was especially striking in the ATP-binding cassette superfamily and did not parallel evolutionary conservation: there was little variation in the TMDs, even in evolutionarily unconserved residues. We used allele frequency distribution to evaluate different scoring systems (Grantham, blosum62, SIFT, and evolutionarily conservedevolutionarily unconserved) for their ability to predict which SNPs affect function. Our underlying assumption was that alleles that are functionally deleterious will be selected against and thus under represented at high frequencies and over represented at low frequencies. We found that evolutionary conservation of orthologous sequences, as assessed by evolutionarily conservedevolutionarily unconserved and SIFT, was the best predictor of allele frequency distribution and hence of function. European Americans had an excess of high frequency alleles in comparison to African Americans, consistent with a historic bottleneck. In addition, African Americans exhibited a much higher frequency of population specific medium-frequency alleles than did European Americans.

DNA↗
PubMed2003

Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection.

The presence of four lysosomal storage diseases (LSDs) at increased frequency in the Ashkenazi Jewish population has suggested to many the operation of natural selection (carrier advantage) as the driving force. We compare LSDs and nonlysosomal storage diseases (NLSDs) in terms of the number of mutations, allele-frequency distributions, and estimated coalescence dates of mutations. We also provide new data on the European geographic distribution, in the Ashkenazi population, of seven LSD and seven NLSD mutations. No differences in any of the distributions were observed between LSDs and NLSDs. Furthermore, no regular pattern of geographic distribution was observed for LSD versus NLSD mutations-with some being more common in central Europe and others being more common in eastern Europe, within each group. The most striking disparate pattern was the geographic distribution of the two primary Tay-Sachs disease mutations, with the first being more common in central Europe (and likely older) and the second being exclusive to eastern Europe (primarily Lithuania and Russia) (and likely much younger). The latter demonstrates a pattern similar to two other recently arisen Lithuanian mutations, those for torsion dystonia and familial hypercholesterolemia. These observations provide compelling support for random genetic drift (chance founder effects, one approximately 11 centuries ago that affected all Ashkenazim and another approximately 5 centuries ago that affected Lithuanians), rather than selection, as the primary determinant of disease mutations in the Ashkenazi population.

Europe↗
PubMed2003

Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide.

The ability to taste the substance phenylthiocarbamide (PTC) has been widely used for genetic and anthropological studies, but genetic studies have produced conflicting results and demonstrated complex inheritance for this trait. We have identified a small region on chromosome 7q that shows strong linkage disequilibrium between single-nucleotide polymorphism (SNP) markers and PTC taste sensitivity in unrelated subjects. This region contains a single gene that encodes a member of the TAS2R bitter taste receptor family. We identified three coding SNPs giving rise to five haplotypes in this gene worldwide. These haplotypes completely explain the bimodal distribution of PTC taste sensitivity, thus accounting for the inheritance of the classically defined taste insensitivity and for 55 to 85% of the variance in PTC sensitivity. Distinct phenotypes were associated with specific haplotypes, which demonstrates that this gene has a direct influence on PTC taste sensitivity and that sequence variants at different sites interact with each other within the encoded gene product.

Alleles↗
PubMed2003

A genome scan for hypertension susceptibility loci in populations of Chinese and Japanese origins.

BACKGROUND: Our understanding of genes that predispose to essential hypertension is poor. METHODS: A genome-wide scan for linkage at approximately 10 cM resolution was done on 1425 sibpairs of Chinese and Japanese origins that were concordant for hypertension (N = 661), low-normal blood pressure (BP) (N = 184), or discordant for BP (N = 580). RESULTS: There was no significant evidence of linkage to a single locus in the genome. There was suggestive evidence of linkage to chromosome 10p, with a LOD score of 2.5. CONCLUSIONS: We can exclude the possibility that a single gene accounts for at least 15% of the variance in hypertension in this population.

Adult↗
PubMed2003

A meta-analysis of genome-wide linkage scans for hypertension: the National Heart, Lung and Blood Institute Family Blood Pressure Program.

BACKGROUND: Four multicenter Networks (GenNet, GENOA, HyperGEN, SAPPHIRe) form the National Heart, Lung and Blood Institute Family Blood Pressure Program (FBPP), to search for hypertension/blood pressure (BP) genes. The networks used different family designs and targeted multiple ethnic groups, using standardized protocols and definitions. Linkage genome scans were done on samples within each network (N = 6245 relatives). METHODS: The evidence was synthesized using meta-analysis. RESULTS: Combining ethnic groups, no region reached LOD >2, but several small peaks were identified, including chromosome 2p where two other recent reports find hypertension linkage. CONCLUSIONS: No regions show uniformly large effects on BP/hypertension in all populations.

Chromosome Mapping↗
PubMed2003

Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease.

The past two decades have witnessed an explosion in the identification, largely by positional cloning, of genes associated with mendelian diseases. The roughly 1,200 genes that have been characterized have clarified our understanding of the molecular basis of human genetic disease. The principles derived from these successes should be applied now to strategies aimed at finding the considerably more elusive genes that underlie complex disease phenotypes. The distribution of types of mutation in mendelian disease genes argues for serious consideration of the early application of a genomic-scale sequence-based approach to association studies and against complete reliance on a positional cloning approach based on a map of anonymous single nucleotide polymorphism haplotypes.

Alleles↗
PubMed2002

A highly significant association between a COMT haplotype and schizophrenia.

Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of (i) a large sample size-to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well defined homogeneous population; and (iii) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype (P=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.

Case-Control Studies↗
PubMed2002

On the twin risk in autism.

Autism is considered by many to be the most strongly genetically influenced multifactorial childhood psychiatric disorder. In the absence of any known gene or genes, the main support for this is derived from family and twin studies. Two recent studies (Greenberg et al. 2001; Betancur et al. 2002) suggested that the twinning process itself is an important risk factor in the development of autism. If true, this would have major consequences for the interpretation of twin studies. Both studies compared the number of affected twin pairs among affected sib pairs to expected values in two separate samples of multiplex families and reported a substantial and significant excess of twin pairs. Using data from our epidemiological study in Western Australia, we investigated the possibility of an increased rate of autism in twins. All children born between 1980 and 1995 with autism, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) were ascertained. Of the 465 children with a diagnosis, 14 were twin births (rate 30.0/1,000) compared to 9,640 children of multiple births out of a total of 386,637 births in Western Australia between 1980 and 1995 (twin rate weighted to number of children with autism or PDD per year 26.3/1,000). These data clearly do not support twinning as a substantial risk factor in the etiology of autism. We demonstrate that the high proportion of twins found in affected-sib-pair studies can be adequately explained by the high ratio of concordance rates in monozygotic (MZ) twins versus siblings and the distribution of family size in the population studied. Our results are in agreement with those of two similar studies by Croen et al. (2002) in California and Hultman et al. (2002) in Sweden.

Australia↗