We have studied 28 kindreds with familial Alzheimer’s disease (FAD) that are all descended from the ethnic group of Germans from Russia. Eighteen families were of Volga German ancestry, originating from the same two villages and... more
We have studied 28 kindreds with familial Alzheimer’s disease (FAD) that are all descended from the ethnic group of Germans from Russia. Eighteen families were of Volga German ancestry, originating from the same two villages and containing 132 demented individuals. Mean age of onset in these 18 families was 61 years, and mean duration of disease to death was 9.5 yrs. The affected persons had clinically and neuropathologically typical Alzheimer’s disease. Nineteen autopsies in eight families demonstrated classic amyloid neuritic plaques, neurofibrillary tangles and amyloid angiopathy. The plaques were β/A4 antibody positive and prion antibody negative. Ten families were of Black Sea German ancestry with 41 affected persons. Mean age of onset in this group was 71.4 years, significantly later than in the Volga German kindreds. There was autopsy documentation of AD in three Black Sea German families. The largest Volga German families showed no evidence of linkage to markers on chromosome 21 and revealed none of the known mutations in the amyloid precursor protein (APP) or PRIP (prion) genes. These families represent a model of genetic heterogeneity when compared with other reported FAD kindreds. Because of their common, isolated ethnic background, the Volga German families are likely to represent the founder effect and a single, as yet unidentified, autosomal dominant mutation. The Black Sea German kindreds may represent additional heterogeneity.
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Molecular linkage analysis was performed on a kindred with X-linked sideroblastic anemia and ataxia. Two-point analysis with a DNA probe for phosphoglycerate kinase (PGK1), which maps to Xq13, suggested linkage to the disorder by a lod... more
Molecular linkage analysis was performed on a kindred with X-linked sideroblastic anemia and ataxia. Two-point analysis with a DNA probe for phosphoglycerate kinase (PGK1), which maps to Xq13, suggested linkage to the disorder by a lod score of at least 2.60 at a recombination fraction of zero. The disease in this kindred appears to be clinically and genetically distinct from that in previously reported families with X-linked hereditary ataxia or spastic paraparesis. No mapping data are available for inherited X-linked sideroblastic anemia without neurologic abnormalities. However, structural alterations of band Xq13 may be involved in the development of idiopathic acquired sideroblastic anemia. No alterations in the restriction patterns of two X-linked genes involved in erythrocyte formation-i.e., a DNA-binding protein (GF-1) and 5-aminolevulinate synthase (ALAS)-were detected in DNA from affected males, arguing against a large deletion in either of these candidate genes.
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Research Interests: Genetics, Biology, Medicine, Multidisciplinary, Neurodegenerative Diseases, and 15 moreAmyotrophic Lateral Sclerosis, Biological Sciences, Humans, Female, Male, Human Molecular Genetics, Guam, Pedigree, Aged, Middle Aged, Adult, Neurodegenerative Disease, Case Control Studies, Medical and Health Sciences, and Genetic predisposition to disease
Genetic factors play a major role in some if not all cases of Alzheimer's disease (AD). In certain rare families, the disease is most likely inherited as an autosomal dominant trait. Identification of the genes involved in AD is... more
Genetic factors play a major role in some if not all cases of Alzheimer's disease (AD). In certain rare families, the disease is most likely inherited as an autosomal dominant trait. Identification of the genes involved in AD is in progress. One AD-related gene, which codes for the amyloid precursor protein (APP), has been cloned and characterized. This gene, though certainly involved in the pathogenesis of AD, is not defective in AD subjects. Genetic linkage analysis of familial Alzheimer's disease (FAD) should help to identify defective genes directly involved in initiating the pathogenesis of AD. In addition, the study of the genes responsible for the Down syndrome (DS) phenotype may yield information on the sequence of events leading to the dementia of AD.
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Individuals in natural populations are surrounded by other organisms of the same and different species. It is clear that at least some aspects of the ensuing interactions are potentially subject to evolutionary modification, but it is not... more
Individuals in natural populations are surrounded by other organisms of the same and different species. It is clear that at least some aspects of the ensuing interactions are potentially subject to evolutionary modification, but it is not clear that such changes always occur. The uncertainty of the occurrence of coevolution is a problem particularly in the study of coadaptation of competitor species. Theoretical models of coevolution indicate that selection will tend to favor decreased interactions between competitors (Levins and Culver, 1971; Allen, 1975, 1976; Lawlor and Maynard Smith, 1976). However, knowledge of the direction in which selection may push a quantitative character does not tell us whether change can or will occur. Current genetic variability determines in part the immediate response to selection, but the long
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In this article we address how the recent, and anticipated upcoming, FDA approvals of novel anti-amyloid medications to treat individuals with mild Alzheimer’s disease (AD) dementia could impact disclosure of biomarker results among... more
In this article we address how the recent, and anticipated upcoming, FDA approvals of novel anti-amyloid medications to treat individuals with mild Alzheimer’s disease (AD) dementia could impact disclosure of biomarker results among asymptomatic research participants. Currently, research is typically the context where an asymptomatic individual may have the option to learn their amyloid biomarker status. Asymptomatic research participants who learn their amyloid status may have questions regarding the meaning of this result and the implications for accessing a potential intervention. After outlining our rationale, we provide examples of how current educational materials used in research convey messages regarding amyloid positivity and the availability of treatments, or lack thereof. We suggest language to improve messaging, as well as strengths of current materials, in addressing these issues for research participants. Although novel medications are currently only approved for use among symptomatic individuals, their availability may have implications for disclosure among asymptomatic research participants with evidence of amyloid deposition, who may be especially interested in information on these interventions for potential prevention, or future treatment, of mild cognitive impairment or dementia due to AD.
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BackgroundIncorporating functional annotations improves power to identify rare variants (RV) in the analysis of whole genome sequencing (WGS) association studies. We incorporated Alzheimer’s Disease (AD)‐specific annotations based on... more
BackgroundIncorporating functional annotations improves power to identify rare variants (RV) in the analysis of whole genome sequencing (WGS) association studies. We incorporated Alzheimer’s Disease (AD)‐specific annotations based on partitioning heritability into the variant‐Set Test for Association using Annotation information (STAAR‐O) framework to identify RVs associated with AD in the diverse sample of the Alzheimer’s Disease Sequencing Project (ADSP).MethodWe performed WGS association analyses in a sample of 4,074 individuals (1,668 AD cases; 2,406 controls) sequenced as part of the ADSP Discovery Extension Phase. We first estimated heritability of all single nucleotide variants in functional annotation categories using the GCTA tool embedded in FunSPU. For each annotation category, a global weight was derived based on the partitioned AD heritability. Among weighted functional scores, we selected the top 12 to leverage the most informative functional annotations for incorporation into the STAAR‐O test.2 We performed agnostic region‐based association analysis using sliding windows, defined as 2kb in length with a skip length of 1kb. Association tests were performed with RV (minor allele frequency <1%), adjusting for sex, sequencing center, platform, study, 4 principal components, and a genetic relatedness matrix. Replication of significant associations was carried out in an independent sample of 10,083 individuals (5,717 AD cases, 4,366 controls) sequenced as part of the ADSP Follow‐Up Study and using the same analytical models.ResultOut of 2.65 million 2‐kb overlapping windows with a total minor allele count >10, two non‐consecutive windows on chromosome 17 were associated with AD (P<5×10−8) (Figures). Both windows associations were replicated in the independent sample (P = 0.003 and 0.016). The top variant of one significant window was rs534148850 (MAF = 0.0005, P = 5.55×10−9) located downstream of PLEKHM1P1, a pseudogene, and MIR4315‐2, a microRNA with predicted targets enriched in apoptosis pathways. The top variant of the other window was rs532055552 (MAF = 0.005, P = 6.20×10−9) located downstream of CEP112, a coiled domain‐containing protein involved in the regulation of gamma‐aminobutyric acid A receptor surface expression.ConclusionIncorporating AD‐relevant functional annotations to a powerful RV association framework, we discovered and replicated two novel genetic regions harboring RV associated with AD.
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Research Interests: Genetics, Human Genetics, Complementary and Alternative Medicine, Biology, Behavioral Medicine, and 15 moreAdolescent, Dyslexia, Language disorders, Developmental dyslexia, Humans, Child, Female, Autism Spectrum Disorder, Aged, Genotype, Adult, Communication sciences and disorders, Child preschool, Endophenotype, and Genetic predisposition to disease
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BackgroundLate‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk factors. Linkage and association analysis have mapped dozens of loci in pooled analysis of many pedigrees or large numbers of unrelated cases... more
BackgroundLate‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk factors. Linkage and association analysis have mapped dozens of loci in pooled analysis of many pedigrees or large numbers of unrelated cases and controls. Identification of the underlying DNA risk variants in the regions of interest (ROIs) has been complicated by both the genetic heterogeneity and the cost, until recently, of comprehensive DNA sequencing in ROIs. The known loci also leave much heritability unexplained.MethodWe used the families in the AD Sequencing Project (ADSP) discovery family sample to identify variants of interest from whole genome sequences (WGS), and through the variants, genes implicated in risk. We used SNP‐based multipoint linkage analysis to identify ROIs with rare VOIs, carrying out analysis without trimming pedigrees. We pursued all ROIs with family‐specific lodmax scores >1.9, reducing the variants of interest by several filters. We carried out pedigree‐b...
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ABSTRACTDyslexia is a common specific learning disability with a strong genetic basis that affects word reading and spelling. An increasing list of loci and genes have been implicated, but analyses to-date investigated only limited... more
ABSTRACTDyslexia is a common specific learning disability with a strong genetic basis that affects word reading and spelling. An increasing list of loci and genes have been implicated, but analyses to-date investigated only limited genomic variation within each locus with no confirmed pathogenic variants. In a collection of >2000 participants in families enrolled at three independent sites, we performed targeted capture and comprehensive sequencing of all exons and some regulatory elements of five candidate dyslexia risk genes (DNAAF4,CYP19A1,DCDC2,KIAA0319andGRIN2B) for which prior evidence of association exists from more than one sample. For each of six dyslexia-related phenotypes we used both individual-single nucleotide polymorphism (SNP) and aggregate testing of multiple SNPs to evaluate evidence for association. We detected no promoter alterations and few potentially deleterious variants in the coding exons, none of which showed evidence of association with any phenotype. A...
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ImportanceSex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent... more
ImportanceSex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele.ObjectiveTo investigate whether sex and race modify APOE ε4 and ε2 associations with cognition.Design, Setting, and ParticipantsThis genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022.Main Outcomes and MeasuresHarmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or AP...
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BackgroundThe Alzheimer’s Disease Sequencing Project (ADSP) seeks to identify genomic variants contributing to increased risk of and/or protection from Alzheimer’s disease (AD) in multi‐ethnic populations. Here we report on statistical... more
BackgroundThe Alzheimer’s Disease Sequencing Project (ADSP) seeks to identify genomic variants contributing to increased risk of and/or protection from Alzheimer’s disease (AD) in multi‐ethnic populations. Here we report on statistical modeling considerations and results from 4707 diverse individuals including 2076 non‐Hispanic White, 1030 Black, 1304 Hispanic, and 297 of other ancestry with whole genome sequencing (WGS) in the ADSP.MethodsA total of 4789 individuals were sequenced across 4 sequencing centers and 2 sequencing platforms. Joint calling was carried out by the ADSP data coordinating center GCAD. We evaluated a series of models to explore technical covariate adjustment related to study, sequencing center, and platform and then performed single variant association analysis for AD status adjusting for principal components associated with AD, technical covariates, and a genetic relatedness matrix, limiting to variants with a minor allele count > 30 and a missingness rate...
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Lp[a] concentrations in nmol/L and apo[a] size isoforms, expressed in terms of the relative number of apo[a] kringle 4 (K4) repeats, were determined in 3959 whites and blacks from four U.S. communities. Plasma Lp[a] analyses were... more
Lp[a] concentrations in nmol/L and apo[a] size isoforms, expressed in terms of the relative number of apo[a] kringle 4 (K4) repeats, were determined in 3959 whites and blacks from four U.S. communities. Plasma Lp[a] analyses were performed by an ELISA method insensitive to apo[a] size heterogeneity and apo[a] size isoforms were determined by high resolution agarose gel electrophoresis. Allele frequencies were estimated by maximum likelihood methods in order to account for the presence of null alleles and coalescence of hands on gels. The apo[a] allele frequencies and phenotype distributions differed significantly between blacks and whites (P < 0.0001). Blacks had a higher relative frequency of the intermediate alleles K4(22) through K4(28) whereas whites had a higher relative frequency of the small alleles K4(17) through K4(24) and large alleles K4(29) through K4(33). The estimated frequency of the null allele was low in both blacks (1.0%) and whites (6.7%). The Lp[a] distribution was less skewed and Lp[a] concentrations were higher in blacks than whites (mean 94 nmol/L and 48 nmol/L, median 74 nmol/L and 20 nmol/L for blacks and whites, respectively). The relationship between apo[a] size and Lp[a] concentration also differed significantly between these two racial groups. For the large polymorphs (> 31 K4 repeats) both blacks and whites exhibited uniformly low Lp[a] values. For the intermediate isoforms K4(20) through K4(30), a considerable range of Lp[a] values was evident in blacks; the median Lp[a] for each isoform increased nearly linearly as the apo[a] size decreased. In contrast in whites there was little change in median Lp[a] concentrations for isoforms K4(20) through K4(30). For the small apo[a] size (< 20 K4) both blacks and whites exhibited high median Lp[a] levels and a wide variation of Lp[a] levels. The major difference in Lp[a] levels between the two racial groups occurred in the intermediate size isoform range of K4(20) through K4(25). In conclusion, whites and blacks differ significantly in Lp[a] concentrations, allele and phenotype frequencies, and in the relationship between apo[a] size isoform and Lp[a] concentration.
Research Interests: Chemistry, Polymorphism, Adolescent, Medicine, Humans, and 15 moreFemale, Male, High Resolution, Adult, Genetic Polymorphism, European Continental Ancestry Group, Lipid, Gel electrophoresis, Lipoprotein a, Allele Frequency, Biochemistry and cell biology, Maximum Likelihood Method, alleles, Gene frequency, and Medical biochemistry and metabolomics
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The epsilon 4 allele of the apolipoprotein E locus (APOE) has been found to be an important predictor of Alzheimer disease (AD). However, linkage analysis has not clarified the role of APOE in the transmission of AD. The results of the... more
The epsilon 4 allele of the apolipoprotein E locus (APOE) has been found to be an important predictor of Alzheimer disease (AD). However, linkage analysis has not clarified the role of APOE in the transmission of AD. The results of the current study provide evidence that the pattern of transmission of memory disorders differs in nuclear families in which the AD-affected proband did carry an epsilon 4 allele versus those families in which the AD-affected proband did not carry an epsilon allele. Further, risk of AD due to APOE genotype in the probands is modified by family history of memory disorders, suggesting gene-by-gene interactions. Family history remained a significant predictor of AD for affected probands with some, but not all, APOE genotypes in a logistic regression analysis. Though nonadditive in the prediction of AD, APOE genotype and family history acted additively in the prediction of age at AD onset. The results of complex segregation analysis were inconsistent with Men...
Research Interests: Genetics, Family, Biology, Family history, Biological Sciences, and 15 moreHumans, Family Environment, Genetic Map, American, Apolipoprotein E, Logistic Regression Analysis, Aged, Genotype, Informing Science, Allele, Alzheimer Disease, Linkage Analysis, Age of Onset, alleles, and Genetic predisposition to disease
We used Monte Carlo Markov chain (MCMC) methods to analyze a quantitative trait, MAO level, and a discrete trait, Collaborative Study on the Genetics of Alcoholism (COGA) alcoholism. Segregation, linkage, and haplotype sharing were... more
We used Monte Carlo Markov chain (MCMC) methods to analyze a quantitative trait, MAO level, and a discrete trait, Collaborative Study on the Genetics of Alcoholism (COGA) alcoholism. Segregation, linkage, and haplotype sharing were analyzed and effects of marker map features were examined. For MAO, modest signals were found on chromosomes 1 and 17 for raw data, and 15 for covariate‐adjusted data. For alcoholism, a strong signal was found on chromosome 1 with modest signals on chromosomes 4 and 10.
Research Interests: Genetics, Genetic Epidemiology, Biology, Medicine, Software, and 15 moreHumans, Markov chains, Genetic Testing, Markov Chain Monte Carlo, Haplotypes, Alcoholism, Female, Male, Genome, Public health systems and services research, Sex Factors, Markov chain, Genetic Markers, Monoamine oxidase, and Monte Carlo Method
Multipoint linkage analysis is an important approach for localizing disease-associated loci in pedigrees. Linkage analysis, however, is sensitive to misspecification of marker allele frequencies. Pedigrees from recently admixed... more
Multipoint linkage analysis is an important approach for localizing disease-associated loci in pedigrees. Linkage analysis, however, is sensitive to misspecification of marker allele frequencies. Pedigrees from recently admixed populations are particularly susceptible to this problem because of the challenge of accurately accounting for population structure. Therefore, increasing emphasis on use of multiethnic samples in genetic studies requires reevaluation of best practices, given data currently available. Typical strategies have been to compute allele frequencies from the sample, or to use marker allele frequencies determined by admixture proportions averaged over the entire sample. However, admixture proportions vary among pedigrees and throughout the genome in a family-specific manner. Here, we evaluate several approaches to model admixture in linkage analysis, providing different levels of detail about ancestral origin. To perform our evaluations, for specification of marker a...
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Human alpha-L-fucosidase is a lysosomal enzyme responsible for hydrolysis of alpha-L-fucoside linkages in fucoglycoconjugates. A single gene, FUCA 1, located on chromosome 1p34.1-1p36.1 encodes for alpha-L-fucosidase activity. To gain... more
Human alpha-L-fucosidase is a lysosomal enzyme responsible for hydrolysis of alpha-L-fucoside linkages in fucoglycoconjugates. A single gene, FUCA 1, located on chromosome 1p34.1-1p36.1 encodes for alpha-L-fucosidase activity. To gain insight into the nature of the molecular defects leading to fucosidosis, we have characterized the genomic structure of FUCA 1. Restriction-endonuclease analysis suggests that at least seven exons dispersed over 22 kb are present in genomic FUCA 1. Two restriction-fragment-length polymorphisms (RFLPs) have been identified in the Caucasian population. The PvuII and BglI RFLPs each have two codominant alleles in Hardy-Weinberg equilibrium. Allele frequencies for the PvuII RFLP are .70/.30, and those for the BglI RFLP .63/.37. Both RFLPs are in strong linkage disequilibrium with each other, with a correlation coefficient of .94. The polymorphism information content (PIC) of the combined DNA markers is .38, high enough to be useful in the prenatal diagnosis of fucosidosis. The combined lod score for linkage between the fucosidosis mutation and FUCA 1 markers in two families was significant at a recombination fraction of 0. This suggests that the fucosidosis mutation resides in FUCA 1.
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The papers in presentation groups 1-3 of Genetic Analysis Workshop 14 (GAW14) compared microsatellite (MS) markers and single-nucleotide polymorphism (SNP) markers for a variety of factors, using multiple methods in both data sets... more
The papers in presentation groups 1-3 of Genetic Analysis Workshop 14 (GAW14) compared microsatellite (MS) markers and single-nucleotide polymorphism (SNP) markers for a variety of factors, using multiple methods in both data sets provided to GAW participants. Group 1 focused on data provided from the Collaborative Study on the Genetics of Alcoholism (COGA). Group 2 focused on data simulated for the workshop. Group 3 contained analyses of both data sets. Issues examined included: information content, signal strength, localization of the signal, use of haplotype blocks, population structure, power, type I error, control of type I error, the effect of linkage disequilibrium, and computational challenges. There were several broad resulting observations. 1) Information content was higher for dense SNP marker panels than for MS panels, and dense SNP markers sets appeared to provide slightly higher linkage scores and slightly higher power to detect linkage than MS markers. 2) Dense SNP panels also gave higher type I errors, suggesting that increased test thresholds may be needed to maintain the correct error rate. 3) Dense SNP panels provided better trait localization, but only in the COGA data, in which the MS markers were relatively loosely spaced. 4) The strength of linkage signals did not vary with the density of SNP panels, once the marker density was approximately 1 SNP/cM. 5) Analyses with SNPs were computationally challenging, and identified areas where improvements in analysis tools will be necessary to make analysis practical for widespread use.
Research Interests: Genetics, Geography, Genetic Epidemiology, Biology, Medicine, and 13 moreHumans, Alcoholism, Microsatellite, Phenotype, Genetic linkage analysis, Snp, Single Nucleotide Polymorphism, Public health systems and services research, Group, Linkage Disequilibrium, Reproducibility of Results, Genetic Analysis, and Linkage Analysis
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BackgroundUsing sequencing from multi‐ethnic AD studies, the ADSP aims to identify genomic variation contributing to elevated risk of, or protection from, AD. We examined coding region variation in the ADSP WES (whole exome sequencing)... more
BackgroundUsing sequencing from multi‐ethnic AD studies, the ADSP aims to identify genomic variation contributing to elevated risk of, or protection from, AD. We examined coding region variation in the ADSP WES (whole exome sequencing) Release 2 dataset, comprising jointly‐called genotypes on 12,135 non‐Hispanic White (NHW), 4,108 African American (AA), and 2,159 Hispanic (HI) samples, to characterize ethnic differences and similarities in AD risk profiles across 40 known AD susceptibility loci.MethodThe ADSP WES Release 2 dataset includes genotype data on 8,789 cases and 9,613 controls collected in nine datasets using 10 target capture kits jointly called by the Genomic Center for Alzheimer’s Disease (GCAD). To test genetic associations, we first combined genotype data that had been QCed (quality‐controlled) by ‘subset’ of source dataset and capture kit, excluded low quality variants and samples, and then stratified by race/ethnicity. Within race/ethnicity, we performed association...
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The Volga Germans (VG) are an ethnically distinct group of 8 families in whom early-onset (mean age-of-onset <60 years) FAD segregates as an autosomal dominant trait, probably due to a founder effect. Known FAD loci are a chromosome... more
The Volga Germans (VG) are an ethnically distinct group of 8 families in whom early-onset (mean age-of-onset <60 years) FAD segregates as an autosomal dominant trait, probably due to a founder effect. Known FAD loci are a chromosome 14q24.3 locus for which the majority of early-onset FAD families show linkage, and the ApoE4 allele of the apolipoprotein E (ApoE) gene on chromosome 19q11.3. Linkage of VG FAD to markers on chromosomes 14, 21 and 19 has been excluded, and no APP mutations were found in affected VG subjects. The VG have an increased frequency of ApoE4 but do not show an association of FAD with the ApoE4 allele. In contrast to late-onset FAD families, ApoE4 does not modify age-of-onset in the VG: mean age-of-onset is 62.2{plus_minus}10.0 years for affected individuals with no ApoE4 alleles, 62.0{plus_minus}6.0 for affecteds homozygous for ApoE4. Therefore FAD in the VG group is caused by a locus which is as yet unidentified. To map this locus we have undertaken a genom...
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Research Interests: Genetics, Developmental Biology, Autism, Biology, Developmental neuroscience, and 15 moreGene expression, Human, Female, Heritability, Autism Spectrum Disorder, Clinical Sciences, Genotyping, DDC, Gene Set Analysis, Chromosomes, Case Control Studies, Genetic Correlation, Adaptor Proteins, Brain Disorders, and Genetic predisposition to disease
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We analyzed a quantitative trait (serum IgE levels), and a binary trait (asthma), in four Hutterite sub‐pedigrees. A genome screen for asthma was performed using GENEHUNTER, and interesting regions were followed up using extended... more
We analyzed a quantitative trait (serum IgE levels), and a binary trait (asthma), in four Hutterite sub‐pedigrees. A genome screen for asthma was performed using GENEHUNTER, and interesting regions were followed up using extended pedigrees and the FASTLINK package. Markov chain Monte Carlo (MCMC) methods were used to assess haplotype sharing among affected individuals (MORGAN/AUTOZYG), and to perform a combined oligogenic segregation and linkage analysis (LOKI) for log10(IgE). We found evidence for at least two susceptibility loci for asthma on chromosome 5, and a QTL for log10(IgE) on chromosome 1. Our analyses demonstrate that using the most complete pedigree structure possible is advisable, with attention to the possibility of heterogeneity among subunits of a very large pedigree. © 2001 Wiley‐Liss, Inc.
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Thirteen phage clones containing low-copy sequences were isolated from a human DNA library and tested for their ability to detect restriction fragment length polymorphisms (RFLPs). Reported are the RFLPs revealed with each clone, all... more
Thirteen phage clones containing low-copy sequences were isolated from a human DNA library and tested for their ability to detect restriction fragment length polymorphisms (RFLPs). Reported are the RFLPs revealed with each clone, all found in frequencies useful for linkage studies. Cytological data are available for five of the 13 clones, with regional assignments made for three of the markers by in situ hybridization. It is concluded that phage clones containing large unique DNA inserts detect multiple RFLPs with high efficiency. An analysis of the relative efficiency of 20 restriction enzymes for detecting single nucleotide changes is discussed by comparing the observed data to those expected on the basis of recognition and potential site frequencies, as computed from the dinucleotide distribution. Finally, in an effort to facilitate linkage studies using polymorphic DNA sequences, experiments were made with pools of probes from various sources.
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This study tests the hypothesis of maternal inheritance of AD in families of 118 subjects with this disorder enrolled in The Consortium to Establish a Registry for Alzheimer's Disease (CERAD).The parental generation included 24... more
This study tests the hypothesis of maternal inheritance of AD in families of 118 subjects with this disorder enrolled in The Consortium to Establish a Registry for Alzheimer's Disease (CERAD).The parental generation included 24 subjects with dementia. Using the Cox proportional hazards model, we found the age-adjusted mother-to-father relative risk to be 2.8 (95% CI, 1.1 to 7.7). Among a subset of 10 families with one affected parent and at least two affected siblings, the ratio of affected mothers-to-fathers was 9:1. These findings support recent studies that found a high mother-to-father ratio among affected parents of subjects with AD. Together, these results suggest maternal inheritance of AD and are consistent with several hypotheses regarding the genetic nature of AD.NEUROLOGY 1996;47: 254-256
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Research Interests: Developmental Biology, Autism, Family, Biology, Biological Sciences, and 15 moreGene Mapping, Female, Article, Genetic linkage analysis, Autism Spectrum Disorder, Copy Number Variation, Adult, Controlled Study, Genetic Architecture, Genetic Analysis, Autistic disorder, genetic risk, Brain Disorders, Chromosome aberrations, and Genetic predisposition to disease
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<b>Copyright information:</b>Taken from "Approaches to mapping genetically correlated complex traits"http://www.biomedcentral.com/1471-2156/4/s1/S71BMC Genetics 2003;4(Suppl 1):S71-S71.Published online 31 Dec... more
<b>Copyright information:</b>Taken from "Approaches to mapping genetically correlated complex traits"http://www.biomedcentral.com/1471-2156/4/s1/S71BMC Genetics 2003;4(Suppl 1):S71-S71.Published online 31 Dec 2003PMCID:PMC1866510. (a) Log10 IR for HDL (heavy dashed); HDLA (heavy solid); HDLAA (light solid); log(TG/HDL) with covariates CV1 and CV2 (dotted); HDLA with covariates CV2 and lnTG (dash-dot); and lnTG with CV1 and CV2 (double dashed). (b) Difference in genotype values for the heterozygote vs. AA homozygote (AB-AA) and BB homozygote vs. AA homozygote (BB-AA) for all iterations with QTL located between 175 and 195 cM, for a run based on HDLA (Table ). Dashed lines indicate positions of dominant models. Positions of markers 11–22 are indicated along the top.
<b>Copyright information:</b>Taken from "Comparison of marker types and map assumptions using Markov chain Monte Carlo-based linkage analysis of COGA data"BMC Genetics 2005;6(Suppl 1):S11-S11.Published online 30 Dec... more
<b>Copyright information:</b>Taken from "Comparison of marker types and map assumptions using Markov chain Monte Carlo-based linkage analysis of COGA data"BMC Genetics 2005;6(Suppl 1):S11-S11.Published online 30 Dec 2005PMCID:PMC1866829. The 50(squares) and 95(circles) percentiles of the Sdistributions at each STRP are shown. Numbers and tick markers on the top axis denote STRPs and their positions. Dotted lines indicate the 50and 95percentiles assuming a normally distributed score.