We have studied 28 kindreds with familial Alzheimer’s disease (FAD) that are all descended from t... 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.
Molecular linkage analysis was performed on a kindred with X-linked sideroblastic anemia and atax... 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.
Genetic factors play a major role in some if not all cases of Alzheimer's disease (AD). I... 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.
Individuals in natural populations are surrounded by other organisms of the same and different sp... 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
In this article we address how the recent, and anticipated upcoming, FDA approvals of novel anti-... 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.
BackgroundIncorporating functional annotations improves power to identify rare variants (RV) in t... 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.
BackgroundLate‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk fa... 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...
ABSTRACTDyslexia is a common specific learning disability with a strong genetic basis that affect... 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...
ImportanceSex differences are established in associations between apolipoprotein E (APOE) ε4 and ... 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...
We have studied 28 kindreds with familial Alzheimer’s disease (FAD) that are all descended from t... 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.
Molecular linkage analysis was performed on a kindred with X-linked sideroblastic anemia and atax... 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.
Genetic factors play a major role in some if not all cases of Alzheimer's disease (AD). I... 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.
Individuals in natural populations are surrounded by other organisms of the same and different sp... 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
In this article we address how the recent, and anticipated upcoming, FDA approvals of novel anti-... 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.
BackgroundIncorporating functional annotations improves power to identify rare variants (RV) in t... 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.
BackgroundLate‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk fa... 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...
ABSTRACTDyslexia is a common specific learning disability with a strong genetic basis that affect... 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...
ImportanceSex differences are established in associations between apolipoprotein E (APOE) ε4 and ... 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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