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Sagiv Shifman

Publications and source records attributed to Sagiv Shifman.

16 recordsLinked to original sources
PubMed2026

Complex genotype-phenotype relationships in neurodevelopmental disorders.

With the advent of sequencing technologies in recent years, hundreds of high-confidence risk genes have been implicated in neurodevelopmental disorders (NDDs). However, individuals carrying pathogenic variants in the same gene frequently exhibit diverse clinical presentations, including varied symptoms and diagnoses. We propose that this heterogeneity arises from different interacting factors that modulate the phenotypic outcomes of pathogenic variants, including variant-level features, modifying variation across the genome, prenatal and early-life environmental exposures, and developmental noise. Resolving these factors requires integrative approaches that combine population-scale genetics and functional genomics with environmental monitoring and quantitative assessments of stochastic developmental variation. Advancing our understanding of these factors is critical to elucidating the etiology of NDDs and improving diagnostic and personalized therapeutic strategies.

Humans↗
PubMed2006

A complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia.

Several lines of evidence have established the presence of an association between a 3-Mb deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs.

Alleles↗
PubMed2006

A high-resolution single nucleotide polymorphism genetic map of the mouse genome.

High-resolution genetic maps are required for mapping complex traits and for the study of recombination. We report the highest density genetic map yet created for any organism, except humans. Using more than 10,000 single nucleotide polymorphisms evenly spaced across the mouse genome, we have constructed genetic maps for both outbred and inbred mice, and separately for males and females. Recombination rates are highly correlated in outbred and inbred mice, but show relatively low correlation between males and females. Differences between male and female recombination maps and the sequence features associated with recombination are strikingly similar to those observed in humans. Genetic maps are available from http://gscan.well.ox.ac.uk/#genetic_map and as supporting information to this publication.

Animals↗
PubMed2005

A survey of the 22q11 microdeletion in a large cohort of schizophrenia patients.

The occurrence of a microdeletion at 22q11 has long been considered to constitute a risk factor for schizophrenia. Higher rates of 22q11 deletions have been reported in cohorts of patients with schizophrenia. In order to estimate the prevalence of the 22q11 deletion in schizophrenia patients more accurately, a screening for 22q11 deletions was conducted on a cohort of 634 schizophrenia patients, the largest sample size screened to date. Seven microsatellites and three SNPs were used to assess the deletion genotype. In cases where all markers were found to be homozygous (hemizygous), the individual was assumed to carry the deletion. The method used here is simple and efficient in comparison with hybridization technologies. Moreover, the rate of false positives is very low (P-value in the range of 10(-4) to 10(-3)). Approximately 1% of the patient cohort was found to carry 22q11 deletions.

Adolescent↗
PubMed2005

Acetylcholinesterase/paraoxonase interactions increase the risk of insecticide-induced Parkinson's disease.

Exposure to agricultural insecticides, together with yet incompletely understood predisposing genotype/phenotype elements, notably increase the risk of Parkinson's disease. Here, we report findings attributing the increased risk in an insecticide-exposed rural area in Israel to interacting debilitating polymorphisms in the ACHE/PON1 locus and corresponding expression variations. Polymorphisms that debilitate PON1 activity and cause impaired AChE overproduction under anticholinesterase exposure were strongly overrepresented in patients from agriculturally exposed areas, indicating that they confer risk of Parkinson's disease. Supporting this notion, serum AChE and PON1 activities were both selectively and significantly lower in patients than in healthy individuals and in carriers of the risky polymorphisms as compared with other Parkinsonian patients. Our findings suggest that inherited interactive weakness of AChE and PON1 expression increases the insecticide-induced occurrence of Parkinson's disease.

Acetylcholinesterase↗
PubMed2005

Strategies for mapping and cloning quantitative trait genes in rodents.

Over the past 15 years, more than 2,000 quantitative trait loci (QTLs) have been identified in crosses between inbred strains of mice and rats, but less than 1% have been characterized at a molecular level. However, new resources, such as chromosome substitution strains and the proposed Collaborative Cross, together with new analytical tools, including probabilistic ancestral haplotype reconstruction in outbred mice, Yin-Yang crosses and in silico analysis of sequence variants in many inbred strains, could make QTL cloning tractable. We review the potential of these strategies to identify genes that underlie QTLs in rodents.

Animals↗
PubMed2005

Further tests of the association between schizophrenia and single nucleotide polymorphism markers at the catechol-O-methyltransferase locus in an Askenazi Jewish population using microsatellite markers.

Association studies are now primarily being conducted with single nucleotide polymorphisms because they are present everywhere in the genome and can be genotyped in "high throughput" formats. Microsatellite markers have a higher degree of polymorphism than single nucleotide polymorphisms and have been widely used in both linkage and association studies of disease. Polymorphic microsatellite markers with several alleles can readily detect linkage disequilibrium but at any given locus there may be differences between single nucleotide polymorphisms and microsatellites in their power to detect linkage disequilibrium because of the evolutionary history of the locus, especially the rate at which both the single nucleotide polymorphisms and microsatellite polymorphisms have mutated and the number of disease mutations and their history. In the current study, we examined the efficiency of microsatellite markers in association analysis by looking at all existent microsatellite markers in the catechol-O-methyltransferase gene region and by genotyping these microsatellites in a large cohort of schizophrenia patients and healthy controls, a subset of a sample where catechol-O-methyltransferase and schizophrenia were found to be associated. We also estimated the levels of linkage disequilibrium between these microsatellites and the previously reported single nucleotide polymorphisms (within the catechol-O-methyltransferase gene) found to be associated with schizophrenia. A modest allelic association of P=0.041 was found between schizophrenia and the microsatellite marker D22S944, which was not significant, however, when corrected for all microsatellites tested. Nevertheless, significant linkage disequilibrium was found between this marker and the three single nucleotide polymorphisms within the catechol-O-methyltransferase gene that displayed association with the disease in the previously published research on this sample. Significant linkage disequilibrium was also observed between microsatellites up to approximately 300 kb distant from those single nucleotide polymorphisms. Although significant, the extent of linkage disequilibrium in terms of r2 was small (in the order of 0.01).

Base Sequence↗
PubMed2004

Mouse inbred strain sequence information and yin-yang crosses for quantitative trait locus fine mapping.

The shared ancestry of mouse inbred strains, together with the availability of sequence and phenotype information, is a resource that can be used to map quantitative trait loci (QTL). The difficulty in using only sequence information lies in the fact that in most instances the allelic state of the QTL cannot be unambiguously determined in a given strain. To overcome this difficulty, the performance of multiple crosses between various inbred strains has been proposed. Here we suggest and evaluate a general approach, which consists of crossing the two strains used initially to map the QTL and any new strain. We have termed these crosses "yin-yang," because they are complementary in nature as shown by the fact that the QTL will necessarily segregate in only one of the crosses. We used the publicly available SNP database of chromosome 16 to evaluate the mapping resolution achievable through this approach. Although on average the improvement of mapping resolution using only four inbred strains was relatively small (i.e., reduction of the QTL-containing interval by half at most), we found a great degree of variability among different regions of chromosome 16 with regard to mapping resolution. This suggests that with a large number of strains in hand, selecting a small number of strains may provide a significant contribution to the fine mapping of QTL.

Alleles↗
PubMed2004

COMT: a common susceptibility gene in bipolar disorder and schizophrenia.

A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits.

Bipolar Disorder↗
PubMed2003

Linkage disequilibrium patterns of the human genome across populations.

We studied the patterns of linkage disequilibrium (LD) in the human genome among three populations: African Americans, Caucasians and Ashkenazi Jews. These three populations represent admixed, outbred and isolated populations, respectively. The study examined defined chromosomal regions across the whole genome. We found that SNP allele frequencies are highly correlated between Ashkenazi Jews and Caucasians and somewhat distinct in African Americans. In addition, Ashkenazi Jews have a modest increase in LD compared with Caucasians, and both have greater LD than African Americans. The three populations differed more significantly with regard to haplotype heterogeneity. We found, as expected, that Ashkenazi Jews display the greatest extent of homogeneity and African Americans the greatest extent of heterogeneity. We found that most of the variance in LD can be attributed to the difference between regions and markers rather than to that between different population types. The average recombination rates estimated by low-resolution genetic maps can only explain a small fraction of the variance between regions. We found that LD (in terms of r(2)) decreases as a function of distance even within the so-called 'haplotype blocks'. This has significant consequences when using LD mapping for the genetic dissection of complex traits, as higher density SNP maps will be required to scan the genome.

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

Quantitative technologies for allele frequency estimation of SNPs in DNA pools.

We have compared several genotyping methods to assess their applicability to single nucleotide polymorphism (SNP) allele frequency estimation in DNA pools. The accuracy of these methods (restriction fragment length polymorphism, real-time pyrophosphate DNA sequencing, single base extension with fluorescently labeled ddNTPs, homogeneous 5'-nuclease assay, and MALDI-TOF mass spectrometry) was tested by calculating the standard deviation among heterozygous individuals (which are natural DNA pools with 50% representation of each allele) and by estimating allele frequency in artificial pools. We show that although the methods differ in their accuracy, they can all serve for quantification of allele frequency in DNA pools with reasonable accuracy. We found that the influence of the error variance attributed to pool construction on quantification accuracy is insignificant and is SNP dependent.

Algorithms↗
PubMed2002

Power and efficiency of the TDT and case-control design for association scans.

Sample size required for the TDT and the case-control designs was studied for marker-based genome-wide scans for disease association. The influence of various parameters on sample size required to attain a given level of power was analyzed in detail. Small genotypic relative risks, low levels of linkage disequilibrium, and departure from equal frequencies for the disease allele and associated marker allele, significantly and similarly increase sample size required by either the TDT or case-control design. Under the case-control paradigm, we show that the optimal strategy will often be to collect many more control individuals than disease cases with the optimal ratio depending on the relative cost of acquiring cases as compared to controls. For the TDT, the number of required simplex families is virtually equal to the number of cases required for similar power in case-control studies with an equal number of cases and controls. The case-control approach may therefore prove to be more economical and expeditious than the TDT design for diseases in which the cost and time required to collect simplex families is much greater than that needed to acquire isolated disease cases. Nevertheless, possible population stratification needs to be addressed when the case-control design is applied.

Case-Control Studies↗
PubMed2002

Genetic dissection of common diseases.

The complex genetic nature of many common diseases makes the identification of the genes that predispose to these ailments a difficult task. In this review we discuss the elements that contribute to the complexity of polygenic diseases and describe an experimental strategy for disease-related gene discovery that attempts to overcome these factors. This strategy involves a population-based case-control paradigm and makes use of a highly informative, homogeneous founder population, many of whose members presently reside in Israel. The properties of single nucleotide polymorphisms, which are presently the markers of choice, are discussed, and the technologies that are currently available for SNP genotyping are briefly presented.

Case-Control Studies↗
PubMed2001

Population-based gene discovery in the post-genomic era.

The complex genetic nature of many common diseases makes the identification of the genes that predispose to these ailments a difficult task. Consequently, many factors have to be considered in choosing the optimal approach to be taken in gene discovery of susceptibility genes. The elements to be considered include the applicability of a family-based linkage paradigm versus a population-based association design and the effects of linkage disequilibrium (LD) and genotypic relative risk (GRR). In this review we discuss these various points and describe the impact on LD and GRR of studying an isolated (also termed 'founder' or 'homogeneous') population, such as Ashkenazi Jews, as compared to an outbred population, such as Caucasians.

Journal Article↗