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1.  Association of Single-Nucleotide Polymorphisms of the Tau Gene With Late-Onset Parkinson Disease 
Context
The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease.
Objective
To investigate whether the tau gene is involved in idiopathic PD.
Design, Setting, and Participants
Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene.
Main Outcome Measure
Family-based tests of association, calculated using asymptotic distributions.
Results
Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype (P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3,9i, 9ii, and 11).
Conclusions
This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.
PMCID: PMC3973175  PMID: 11710889
2.  Alzheimer’s Disease Susceptibility Genes APOE and TOMM40, and Hippocampal Volumes in the Lothian Birth Cohort 1936  
PLoS ONE  2013;8(11):e80513.
The APOE ε and TOMM40 rs10524523 (‘523’) variable length poly-T repeat gene loci have been significantly and independently associated with Alzheimer’s disease (AD) related phenotypes such as age of clinical onset. Hippocampal atrophy has been significantly associated with memory impairment, a characteristic of AD. The current study aimed to test for independent effects of APOE ε and TOMM40 ‘523’ genotypes on hippocampal volumes as assessed by brain structural MRI in a relatively large sample of community-dwelling older adults. As part of a longitudinal study of cognitive ageing, participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε2/ε3/ε4 status and TOMM40 ‘523’ poly-T repeat length, and detailed structural brain MRI at a mean age of 72.7 years (standard deviation = 0.7, N range = 624 to 636). No significant effects of APOE ε or TOMM40 523 genotype were found on hippocampal volumes when analysed raw, or when adjusted for either intracranial or total brain tissue volumes. In summary, in a large community-dwelling sample of older adults, we found no effects of APOE ε or TOMM40 523 genotypes on hippocampal volumes. This is discrepant with some previous reports of significant association between APOE and left/right hippocampal volumes, and instead echoes other reports that found no association. Previous significant findings may partly reflect type 1 error. Future studies should carefully consider: 1) their specific techniques in adjusting for brain size; 2) assessing more detailed sub-divisions of the hippocampal formation; and 3) testing whether significant APOE-hippocampal associations are independent of generalised brain atrophy.
doi:10.1371/journal.pone.0080513
PMCID: PMC3829876  PMID: 24260406
3.  Longitudinal Modeling of Cognitive Aging and the TOMM40 Effect 
Background
TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21–29 T residues) poly-T variants within intron 6 of TOMM40 while APOE e3 can be associated with either with a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer’s disease (AD) onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline.
Methods
An APOE e4 enriched cohort of 639 cognitively normal individuals age 21–97 years of known TOMM40 genotype underwent longitudinal neuropsychological testing every two years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross sectional and longitudinal effects of age on the auditory verbal learning test long term memory score (AVLT) by APOE, TOMM40, and the interaction between the two.
Results
There were significant effects overall for both TOMM40 (p=0.04 linear effect, p=0.03 quadratic effect) and APOE (p=0.06 linear effect, p=0.008 quadratic effect) with no significant interaction (p=0.63). These differences were age-dependent: there was a significant TOMM40 effect prior to age 60 (p=0.009) characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect; and a significant APOE effect after age 60 (p=0.006) characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect.
Conclusion
Both TOMM40 and APOE significantly influence age-related memory performance, but appear to do so independently of each other.
doi:10.1016/j.jalz.2011.11.006
PMCID: PMC3483561  PMID: 23102119
TOMM40; APOE; preclinical Alzheimer’s disease; cognitive aging; age-related memory loss; mitochondria; very long term memory; test-retest effects
4.  A homopolymer polymorphism in the TOMM40 gene contributes to cognitive performance in aging 
Introduction
A highly polymorphic T-homopolymer was recently discovered to be associated with late onset Alzheimer’s disease (LOAD) risk and age of onset.
Objective
To explore the effects of the polymorphic polyT tract (rs10524523, referred as ‘523’) on cognitive performance in cognitively healthy elderly.
Methods
181 participants were recruited from local independent-living retirement communities. Informed consent was obtained and participants completed demographic questionnaires, a conventional paper and pencil neuropsychological battery, and the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB). Saliva samples were collected for determination of the TOMM40 ‘523’ (S, L, VL) and the APOE (ε2, 3, 4) genotypes. From the initial sample of 181 individuals, 127 participants were eligible for the association analysis. Participants were divided into three groups based on ‘523’ genotypes (S/S, S/L-S/VL, and L/L-L/VL-VL/VL) Generalized linear models were used to evaluate the association between the ‘523’ genotypes and neuropsychological test performance. Analyses were adjusted for age, sex, education, depression, and APOE ε4 status. A planned sub analysis was undertaken to evaluate the association between ‘523’ genotypes and test performance in a sample restricted to APOE ε3 homozygotes.
Results
The S homozygotes performed better, although not significantly, than the S/L-S/VL and the VL/L-L/VL-VL/VL genotype groups on measures associated with memory (CANTAB Paired-Associate Learning, and VRM Free Recall) and executive function (CANTAB measures of Intra-Extradimensional set shifting). Follow-up analysis of APOEε 3 homozygotes only, showed that the S/S group performed significantly better than the S/VL group on measures of episodic memory (CANTAB Paired-Associate Learning and VRM Free Recall), attention (CANTAB RVP Latency) and executive function (Digit-Symbol substitution). The S/S group performed marginally better than the VL/VL group on Intra-Extradimensional set shifting. None of the associations remained significant after applying a Bonferroni correction for multiple testing.
Conclusions
Results suggest important APOE-independent associations between the TOMM40 ‘523’ polymorphism and specific cognitive domains of memory and executive control that are preferentially affected in early stage AD.
doi:10.1016/j.jalz.2011.10.005
PMCID: PMC3438346  PMID: 22863908
TOMM40; polyT polymorphism; cognition; aging; neuropsychological tests; CANTAB; Alzheimer’s disease
5.  The Effect of TOMM40 Poly-T length on Gray Matter Volume and Cognition in Middle-Aged Persons with APOE ε3/ε3 Genotype 
Objective
Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late onset Alzheimer’s disease (LOAD), with APOE ε4 having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the TOMM40 gene has been shown to influence age of onset in LOAD, with very long poly-T length associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism.
Methods
Among N=117 healthy APOE ε3 homozygous adults (mean age 55), we compared those homozygous for very long (VL/VL; n=35) TOMM40 poly-T lengths (who are presumably at higher risk) to those homozygous for short (S/S; n=38) poly-T lengths, as well as those with heterozygous (S/VL; n=44) poly-T length polymorphisms, on measures of learning and memory and on structural brain imaging.
Results
The VL/VL group exhibited lower performance than the S/S TOMM40 group on primacy retrieval from a verbal list learning task, a finding which is also seen in early AD. A dose-dependent increase in the VL TOMM40 polymorphism (from no VL alleles, to S/VL heterozygous, to VL/VL homozygous) was associated with decreasing gray matter volume in the ventral posterior cingulate and medial ventral precuneus, a region of the brain affected early in LOAD.
Conclusions
These findings among APOE ε3/ε3 late middle-aged adults suggest that a subgroup with very long TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes.
doi:10.1016/j.jalz.2010.11.012
PMCID: PMC3143375  PMID: 21784354
6.  Characterization of the Poly-T Variant in the TOMM40 Gene in Diverse Populations 
PLoS ONE  2012;7(2):e30994.
We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined for rs10524523, hereafter ‘523’, based on the number of ‘T’-residues: ‘Short’ (S, T≤19), ‘Long’ (L, 20≤T≤29) and ‘Very Long’ (VL, T≥30). Homopolymers, particularly long homopolymers like ‘523’, are difficult to genotype because ‘slippage’ occurs during PCR-amplification. We initially genotyped this locus by PCR-amplification followed by Sanger-sequencing. However, we recognized the need to develop a higher-throughput genotyping method that is also accurate and reliable. Here we describe a new ‘523’ genotyping assay that is simple and inexpensive to perform in a standard molecular genetics laboratory. The assay is based on the detection of differences in PCR-fragment length using capillary electrophoresis. We discuss technical problems, solutions, and the steps taken for validation. We employed the novel assay to investigate the ‘523’ allele frequencies in different ethnicities. Whites and Hispanics have similar frequencies of S/L/VL alleles (0.45/0.11/0.44 and 0.43/0.09/0.48, respectively). In African-Americans, the frequency of the L-allele (0.10) is similar to Whites and Hispanics; however, the S-allele is more prevalent (0.65) and the VL-allele is concomitantly less frequent (0.25). The allele frequencies determined using the new methodology are compared to previous reports for Ghanaian, Japanese, Korean and Han Chinese cohorts. Finally, we studied the linkage pattern between TOMM40-‘523’ and APOE alleles. In Whites and Hispanics, consistent with previous reports, the L is primarily linked to ε4, while the majority of the VL and S are linked to ε3. Interestingly, in African-Americans, Ghanaians and Japanese, there is an increased frequency of the ‘523’S-APOEε4 haplotype. These data may be used as references for ‘523’ allele and ‘523’-APOE haplotype frequencies in diverse populations for the design of research studies and clinical trials.
doi:10.1371/journal.pone.0030994
PMCID: PMC3281049  PMID: 22359560
7.  Genetic and clinical implications of a variable poly-T repeat within the TOMM40 gene for late-onset Alzheimer's disease 
Archives of neurology  2010;67(5):536-541.
I coauthored a recently published research paper demonstrating that a variable length, poly-T polymorphism in the TOMM40 (Translocase of the Outer Mitochondrial Membrane 40 homolog (yeast)) gene, which lies adjacent to APOE on chromosome 19, accounts for the age of onset distribution for a complex disease, late-onset Alzheimer's disease (LOAD).1 These new data explain the average age of disease onset for patients with the APOE4/4 genotype, and differentiate two forms of TOMM40 poly-T polymorphisms linked to APOE with each form associated with a different age of disease onset distribution.2 When linked to APOE3, the longer TOMM40 poly-T repeats (19–39 nucleotides) at the rs10524523 (523) locus are associated with earlier age of onset and shorter TOMM40 alleles (11–16 nucleotides) with later onset. The data suggest that the poly-T alleles are co-dominant, with the age of onset phenotype determined by both of the two inherited alleles but with variable expressivity. Additional data will further refine the relationship between the length of the poly-T alleles and age of disease onset and determine if the relationship is linear.
doi:10.1001/archneurol.2010.88
PMCID: PMC3140162  PMID: 20457951
8.  Genetic variation at a single locus and age of onset for Alzheimer’s Disease 
This perspective article is an opportunity to explain a new genetic finding for late-onset Alzheimer s disease (LOAD). This invited perspective is specifically writtenfor physicians and scientists who are interested in LOAD, but it may be relevant to those interested in identifying susceptibility variants for other complex diseases. The significant finding discussed here is that a variable–length, deoxythymidine homopolymer (poly-T) within intron 6 of the TOMM40 gene is associated with the age of onset of LOAD [3]. This result was obtained with a phylogenetic study of the genetic polymorphisms that reside within the linkage disequilibrium [LD] block that contains TOMM40, APOE, and APOC1 genes on each chromosome from patients with LOAD and age-matched subjects without disease. While the data will have diagnostic, prognostic and therapeutic strategy implications, this perspective is meant to place the inheritance pattern for this complex human disease into context, and to highlight the potential utility of applying phylogenetic tools to the study of the genetics of complex diseases.
doi:10.1016/j.jalz.2010.01.011
PMCID: PMC2874876  PMID: 20298972
9.  Alzheimer’s disease: diagnostics, prognostics and the road to prevention 
The Epma Journal  2010;1(2):293-303.
Alzheimer’s disease (AD) presents one of the leading healthcare challenges of the 21st century, with a projected worldwide prevalence of >107 million cases by 2025. While biomarkers have been identified, which may correlate with disease progression or subtype for the purpose of disease monitoring or differential diagnosis, a biomarker for reliable prediction of late onset disease risk has not been available until now. This deficiency in reliable predictive biomarkers, coupled with the devastating nature of the disease, places AD at a high priority for focus by predictive, preventive and personalized medicine. Recent data, discovered using phylogenetic analysis, suggest that a variable length poly-T sequence polymorphism in the TOMM40 gene, adjacent to the APOE gene, is predictive of risk of AD age-of-onset when coupled with a subject’s current age. This finding offers hope for reliable assignment of disease risk within a 5-7 year window, and is expected to guide enrichment of clinical trials in order to speed development of preventative medicines.
doi:10.1007/s13167-010-0024-3
PMCID: PMC2987528  PMID: 21124753
Alzheimer’s disease; Personalized medicine; Phylogenetic analysis; Translocase of outer mitochondrial membrane (TOMM40); Apolipoprotein E; Poly-T variant
10.  Genome-Wide Scan of Copy Number Variation in Late-Onset Alzheimer’s Disease 
Alzheimer’s disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE ε4 risk allele, identified a novel variant that influences disease risk within the APOE ε4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer’s disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In line with previous reports, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation.
doi:10.3233/JAD-2010-1212
PMCID: PMC2883723  PMID: 20061627
Alzheimer’s disease; copy number variation; dementia; genome-wide association study
11.  The Knockout Mouse Project 
Nature genetics  2004;36(9):921-924.
Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.
doi:10.1038/ng0904-921
PMCID: PMC2716027  PMID: 15340423
13.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci 
PLoS Genetics  2009;5(3):e1000421.
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.
Author Summary
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association study (GWAS) in COPD. We conducted a GWAS in a homogenous case-control cohort from Norway and evaluated the top 100 single nucleotide polymorphisms in the family-based International COPD Genetics Network. The polymorphisms that showed replication were further evaluated in subjects from the US National Emphysema Treatment Trial and controls from the Normative Aging Study and then in a fourth cohort of extended pedigrees from the Boston Early-Onset COPD population. Two polymorphisms in the α-nicotinic acetylcholine receptor 3/5 locus on chromosome 15 showed unambiguous evidence of association with COPD. This locus has previously been implicated in both smoking behavior and risk of lung cancer, suggesting the possibility of multiple functional polymorphisms in the region or a single polymorphism with wide phenotypic consequences. The hedgehog interacting protein (HHIP) locus on chromosome 4, which is associated with COPD, is also a significant risk locus for COPD.
doi:10.1371/journal.pgen.1000421
PMCID: PMC2650282  PMID: 19300482
14.  A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia 
PLoS Genetics  2009;5(2):e1000373.
We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater “load” of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.
Author Summary
Schizophrenia is a highly heritable disease. While the drugs commonly used to treat schizophrenia offer important relief from some symptoms, other symptoms are not well treated, and the drugs cause serious adverse effects in many individuals. This has fueled intense interest over the years in identifying genetic contributors to schizophrenia. In this paper, we first show that common genetic variants, the focus of most research until recently, do not seem to have a major impact on schizophrenia predisposition. We then provide further evidence that very rare, large DNA deletions and duplications contribute to or explain a minority of schizophrenia cases. Although the small number of events identified here do not restrict focus to a finite set of molecular pathways, we do show one event that deletes a gene known to interact with DISC1, a gene known to cause psychiatric problems in one family. Such convergent findings have potential implications for the development of new therapies and patient subclassifications. We conclude that schizophrenia genetics research must turn sharply toward the identification of rare genetic contributors and that the most important tool in this effort will be complete whole-genome sequencing of patients whose clinical characteristics have been very thoroughly assessed.
doi:10.1371/journal.pgen.1000373
PMCID: PMC2631150  PMID: 19197363
15.  Inhibition of α-ketoglutarate-and pyruvate dehydrogenase complexes in E. coli by a glutathione S-transferase containing a pathological length poly-Q domain: A possible role of energy deficit in neurological diseases associated with poly-Q expansions? 
Age  1998;21(1):25-30.
At least seven adult-onset neurodegenerative diseases, including Huntington’s disease (HD), are caused by genes containing expanded CAG triplets within their coding regions. The expanded CAG repeats give rise to extended stretches of polyglutamines (Qn) in the proteins expressed by the affected genes. Generally, n ≥40 in affected individuals and ≤36 in clinically unaffected individuals. The expansion has been proposed to confer a “toxic gain of function” to the mutated protein. Poly-Q domains have recently been shown to be excellent substrates of tissue transglutaminase. We investigated the effects of expression of glutathione S-transferase constructs containing poly-Q inserts of various lengths (GSTQn where n = 0, 10, 62 or 81) on the activity of some key metabolic enzymes in the host Escherischia coil-an organism not known to have transglutaminase activity. E. coil carrying the GSTQ62 construct exhibited statistically significant decreases in the specific activities of α-ketoglutarate dehydrogenase complex (KGDHC) and pyruvate dehydrogenase complex (PDHC). Previous work has shown that KGDHC and PDHC activities are reduced in the brains of Alzheimer’s disease (AD) patients. Our results suggest that KGDHC and PDHC may be particularly susceptible to the effects of a number of disparate insults, including those associated with AD and HD.
doi:10.1007/s11357-998-0004-x
PMCID: PMC3455770  PMID: 23604331
16.  Correspondence 
Archives of Disease in Childhood  1976;51(12):983-985.
PMCID: PMC1546154

Results 1-16 (16)