ABSTRACT
It has been reported that superior rectus transposition combined with medial rectus recession can provide as good results as transposition of both vertical rectus muscles, with no adverse effects on torsion or postoperative vertical misalignment. Further augmentation of transposition surgery can be achieved through the use of posterior fixation sutures, myopexy and botulinum toxin into the medial rectus. We report a patient with complete bilateral traumatic sixth cranial nerve palsies who underwent sequential superior rectus transposition surgery combined with medial rectus recession. The surgery was augmented with a myopexy (posterior suture joining superior and lateral recti with no scleral fixation) in the first eye and with a posterior fixation suture (with scleral fixation) in the second eye. After the second procedure, despite a significant improvement in horizontal alignment, the patient developed 15 degrees of incyclotorsion which was attributed to the scleral fixation suture. The patient underwent removal of the scleral suture and 3 months postoperatively had a significant reduction in incyclotorsion to 8 degrees; however this continued to be a barrier to fusion. Vertical rectus transposition of superior and inferior recti augmented with posterior scleral fixation sutures is one type of conventional surgery for complete lateral rectus palsy. In more recent times, it has become common to transpose the superior rectus alone along with recession of the contracted medial rectus. This procedure can also be augmented with a posterior fixation suture which may or may not be attached to the sclera. Whilst this surgery has gained popularity it is not without risk as demonstrated by our case in which transposition of the superior rectus was associated with postoperative incyclotorsion. In this case a possible explanation may be the use of a the posterior scleral fixation suture as it did not occur when no scleral fixation was used. Furthermore, removal of the posterior scleral fixation suture did reduce the torsion significantly although it did not eliminate it.
Subject(s)
Abducens Nerve Diseases , Ophthalmologic Surgical Procedures , Humans , Oculomotor Muscles/surgery , Sclera/surgery , Suture Techniques , SuturesABSTRACT
This corrects the article DOI: 10.1038/mp.2015.165.
ABSTRACT
We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.
Subject(s)
Bipolar Disorder/genetics , Psychotic Disorders/genetics , Aminopeptidases/genetics , Ankyrins/genetics , Bipolar Disorder/classification , Bipolar Disorder/psychology , Calcium Channels, L-Type/genetics , Calmodulin-Binding Proteins/genetics , Case-Control Studies , Chromosomes, Human, Pair 10/genetics , Cytoskeletal Proteins , Genome-Wide Association Study , Genotype , Humans , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Phenotype , Polymorphism, Single Nucleotide , Psychotic Disorders/psychologyABSTRACT
Large (>100 kb), rare (<1% in the population) copy number variants (CNVs) have been shown to confer risk for schizophrenia (SZ), but the findings for bipolar disorder (BD) are less clear. In a new BD sample from the United Kingdom (n=2591), we have examined the occurrence of CNVs and compared this with previously reported samples of 6882 SZ and 8842 control subjects. When combined with previous data, we find evidence for a contribution to BD for three SZ-associated CNV loci: duplications at 1q21.1 (P=0.022), deletions at 3q29 (P=0.03) and duplications at 16p11.2 (P=2.3 × 10(-4)). The latter survives multiple-testing correction for the number of recurrent large CNV loci in the genome. Genes in 20 regions (total of 55 genes) were enriched for rare exonic CNVs among BD cases, but none of these survives correction for multiple testing. Finally, our data provide strong support for the hypothesis of a lesser contribution of very large (>500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10(-4)).
Subject(s)
Bipolar Disorder/genetics , DNA Copy Number Variations , Female , Genotyping Techniques , Humans , Male , Middle Aged , Schizophrenia/genetics , White PeopleABSTRACT
Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.
Subject(s)
Bipolar Disorder/genetics , Carrier Proteins/genetics , Adult , Antimanic Agents/therapeutic use , Biomarkers, Pharmacological/blood , Bipolar Disorder/metabolism , Carrier Proteins/metabolism , Female , Genetic Predisposition to Disease/genetics , Genetic Variation , Genome-Wide Association Study/methods , Genotype , Humans , Lithium/metabolism , Lithium/therapeutic use , Lithium Compounds/therapeutic use , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Risk Factors , Self Report , Sweden , United KingdomABSTRACT
A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.
Subject(s)
Abnormalities, Multiple/genetics , Chromosome Duplication/genetics , DNA Copy Number Variations/genetics , DiGeorge Syndrome/genetics , Genetic Predisposition to Disease , Schizophrenia/genetics , Abnormalities, Multiple/epidemiology , Chromosomes, Human, Pair 22/genetics , DiGeorge Syndrome/epidemiology , Female , Humans , Male , Schizophrenia/epidemiologyABSTRACT
Genome-wide association studies (GWAS) have identified a number of loci that have strong support for their association with bipolar disorder (BD). The Psychiatric Genome-Wide Association Study (GWAS) Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis of BD GWAS data sets and replication samples identified evidence (P=6.7 × 10â»7, odds ratio (OR)=1.147) of association with the risk of BD at the polymorphism rs9371601 within SYNE1, a gene which encodes nesprin-1. Here we have tested this polymorphism in an independent BD case (n=1527) and control (n=1579) samples, and find evidence for association (P=0.0095) with similar effect sizes to those previously observed in BD (allelic OR=1.148). In a combined (meta) analysis of PGC-BD data (both primary and replication data) and our independent BD samples, we found genome-wide significant evidence for association (P=2.9 × 10â»8, OR=1.104). We have also examined the polymorphism in our recurrent unipolar depression cases (n=1159) and control (n=2592) sample, and found that the risk allele was associated with risk for recurrent major depression (P=0.032, OR=1.118). Our findings add to the evidence that association at this locus influences susceptibility to bipolar and unipolar mood disorders.
Subject(s)
Bipolar Disorder/genetics , Depressive Disorder, Major/genetics , Genetic Predisposition to Disease , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Adult , Cytoskeletal Proteins , Female , Gene Frequency , Genome-Wide Association Study , Genotype , Humans , Male , Middle Aged , Odds Ratio , RecurrenceABSTRACT
We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10(-3) from the BD meta-analysis by Ferreira et al. were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=4.09 × 10(-4)) and 15q14 (rs2172835, P=0.043) but not ANK3 (rs10994336, P=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel GWS associations. First, rs7296288 (P=8.97 × 10(-9), odds ratio (OR)=0.9), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH. Second, rs3818253 (P=3.88 × 10(-8), OR=1.16), an intronic SNP on chromosome 20q11.2 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B.
Subject(s)
Bipolar Disorder/genetics , Genetic Predisposition to Disease/genetics , Alleles , Ankyrins/genetics , Calcium Channels, L-Type/genetics , Case-Control Studies , Female , Genome-Wide Association Study , Genotyping Techniques , Humans , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide/geneticsABSTRACT
BACKGROUND: Recent data provide strong support for a substantial common polygenic contribution (i.e. many alleles each of small effect) to genetic susceptibility for schizophrenia and overlapping susceptibility for bipolar disorder. AIMS: To test hypotheses about the relationship between schizophrenia and psychotic types of bipolar disorder. METHOD: Using a polygenic score analysis to test whether schizophrenia polygenic risk alleles, en masse, significantly discriminate between individuals with bipolar disorder with and without psychotic features. The primary sample included 1829 participants with bipolar disorder and the replication sample comprised 506 people with bipolar disorder. RESULTS: The subset of participants with Research Diagnostic Criteria schizoaffective bipolar disorder (n = 277) were significantly discriminated from the remaining participants with bipolar disorder (n = 1552) in both the primary (P = 0.00059) and the replication data-sets (P = 0.0070). In contrast, those with psychotic bipolar disorder as a whole were not significantly different from those with non-psychotic bipolar disorder in either data-set. CONCLUSIONS: Genetic susceptibility influences at least two major domains of psychopathological variation in the schizophrenia-bipolar disorder clinical spectrum: one that relates to expression of a 'bipolar disorder-like' phenotype and one that is associated with expression of 'schizophrenia-like' psychotic symptoms.
Subject(s)
Bipolar Disorder/genetics , Genetic Predisposition to Disease , Multifactorial Inheritance , Phenotype , Schizophrenia/genetics , Adolescent , Alleles , Bipolar Disorder/diagnosis , Case-Control Studies , Diagnostic and Statistical Manual of Mental Disorders , Genetic Linkage , Genotype , Humans , International Classification of Diseases , Logistic Models , Polymorphism, Single Nucleotide , Psychotic Disorders/diagnosis , Psychotic Disorders/genetics , Schizophrenia/diagnosis , United KingdomABSTRACT
We previously performed a linkage study using families identified through probands meeting criteria for DSM-IV schizoaffective disorder, bipolar type (SABP) and observed a genome-wide significant signal (LOD = 3.54) at chromosome 1q42 close to DISC1. An initial sequencing study of DISC1 using 14 unrelated DSM-IV SABP samples from the linkage study identified 2 non-synonymous coding SNPs in exon 11 in 2 separate individuals. Here we provide evidence of additional rare coding SNPs within exon 11. In sequencing exon 11 in 506 cases and 1,211 controls for variants that occurred only once, 4 additional rare variants were found in cases (P-value = 0.008, Fisher's exact trend test).
Subject(s)
Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide , Psychotic Disorders/genetics , Bipolar Disorder/genetics , Case-Control Studies , Exons , Genetic Linkage , Genetic Predisposition to Disease , Humans , Mutation, MissenseABSTRACT
Molecular genetic analysis offers opportunities to advance our understanding of the nosological relationship between psychiatric diagnostic categories in general, and the mood and psychotic disorders in particular. Strong evidence (P=7.0 × 10(-7)) of association at the polymorphism rs1006737 (within CACNA1C, the gene encoding the α-1C subunit of the L-type voltage-gated calcium channel) with the risk of bipolar disorder (BD) has recently been reported in a meta-analysis of three genome-wide association studies of BD, including our BD sample (N=1868) studied within the Wellcome Trust Case Control Consortium. Here, we have used our UK case samples of recurrent major depression (N=1196) and schizophrenia (N=479) and UK non-psychiatric comparison groups (N=15316) to examine the spectrum of phenotypic effect of the bipolar risk allele at rs1006737. We found that the risk allele conferred increased risk for schizophrenia (P=0.034) and recurrent major depression (P=0.013) with similar effect sizes to those previously observed in BD (allelic odds ratio â¼1.15). Our findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined. Our findings will contribute to a better understanding of the pathogenesis of major psychiatric illness, and such knowledge should be useful in providing an etiological rationale for shaping psychiatric nosology, which is currently reliant entirely on descriptive clinical data.
Subject(s)
Bipolar Disorder , Calcium Channels, L-Type/genetics , Depressive Disorder, Major , Schizophrenia , Adult , Alleles , Bipolar Disorder/classification , Bipolar Disorder/epidemiology , Bipolar Disorder/genetics , Depressive Disorder, Major/classification , Depressive Disorder, Major/epidemiology , Depressive Disorder, Major/genetics , Female , Genotype , Humans , Male , Middle Aged , Phenotype , Recurrence , Risk Factors , Schizophrenia/classification , Schizophrenia/epidemiology , Schizophrenia/genetics , United Kingdom/epidemiologyABSTRACT
Despite compelling evidence for a major genetic contribution to risk of bipolar mood disorder, conclusive evidence implicating specific genes or pathophysiological systems has proved elusive. In part this is likely to be related to the unknown validity of current phenotype definitions and consequent aetiological heterogeneity of samples. In the recent Wellcome Trust Case Control Consortium genome-wide association analysis of bipolar disorder (1868 cases, 2938 controls) one of the most strongly associated polymorphisms lay within the gene encoding the GABA(A) receptor beta1 subunit, GABRB1. Aiming to increase biological homogeneity, we sought the diagnostic subset that showed the strongest signal at this polymorphism and used this to test for independent evidence of association with other members of the GABA(A) receptor gene family. The index signal was significantly enriched in the 279 cases meeting Research Diagnostic Criteria for schizoaffective disorder, bipolar type (P=3.8 x 10(-6)). Independently, these cases showed strong evidence that variation in GABA(A) receptor genes influences risk for this phenotype (independent system-wide P=6.6 x 10(-5)) with association signals also at GABRA4, GABRB3, GABRA5 and GABRR3. [corrected] Our findings have the potential to inform understanding of presentation, pathogenesis and nosology of bipolar disorders. Our method of phenotype refinement may be useful in studies of other complex psychiatric and non-psychiatric disorders.
Subject(s)
Bipolar Disorder/genetics , Genetic Predisposition to Disease , Phenotype , Polymorphism, Single Nucleotide/genetics , Receptors, GABA-A/genetics , Adolescent , Adult , Aged , Chromosomes, Human, Pair 4 , Female , Gene Frequency , Genome-Wide Association Study/methods , Humans , Male , Middle Aged , Statistics as Topic , Young AdultABSTRACT
BACKGROUND: Psychiatric phenotypes are currently defined according to sets of descriptive criteria. Although many of these phenotypes are heritable, it would be useful to know whether any of the various diagnostic categories in current use identify cases that are particularly helpful for biological-genetic research. AIMS: To use genome-wide genetic association data to explore the relative genetic utility of seven different descriptive operational diagnostic categories relevant to bipolar illness within a large UK case-control bipolar disorder sample. METHOD: We analysed our previously published Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder genome-wide association data-set, comprising 1868 individuals with bipolar disorder and 2938 controls genotyped for 276 122 single nucleotide polymorphisms (SNPs) that met stringent criteria for genotype quality. For each SNP we performed a test of association (bipolar disorder group v. control group) and used the number of associated independent SNPs statistically significant at P<0.00001 as a metric for the overall genetic signal in the sample. We next compared this metric with that obtained using each of seven diagnostic subsets of the group with bipolar disorder: Research Diagnostic Criteria (RDC): bipolar I disorder; manic disorder; bipolar II disorder; schizoaffective disorder, bipolar type; DSM-IV: bipolar I disorder; bipolar II disorder; schizoaffective disorder, bipolar type. RESULTS: The RDC schizoaffective disorder, bipolar type (v. controls) stood out from the other diagnostic subsets as having a significant excess of independent association signals (P<0.003) compared with that expected in samples of the same size selected randomly from the total bipolar disorder group data-set. The strongest association in this subset of participants with bipolar disorder was at rs4818065 (P = 2.42 x 10(-7)). Biological systems implicated included gamma amniobutyric acid (GABA)(A) receptors. Genes having at least one associated polymorphism at P<10(-4) included B3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTPRG, GIRK2 and CDH12. CONCLUSIONS: Our findings show that individuals with broadly defined bipolar schizoaffective features have either a particularly strong genetic contribution or that, as a group, are genetically more homogeneous than the other phenotypes tested. The results point to the importance of using diagnostic approaches that recognise this group of individuals. Our approach can be applied to similar data-sets for other psychiatric and non-psychiatric phenotypes.
Subject(s)
Bipolar Disorder/genetics , Polymorphism, Single Nucleotide/genetics , Psychotic Disorders/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Bipolar Disorder/diagnosis , Case-Control Studies , Female , Genome-Wide Association Study , Genotype , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Psychotic Disorders/diagnosis , Young AdultSubject(s)
Chromosomes, Human, Pair 15 , Dyslexia/genetics , Genetic Markers , Adolescent , Child , Genetic Predisposition to Disease , HumansABSTRACT
OBJECTIVE: To investigate the impact of possession of the -889 C/T polymorphism of the interleukin 1A gene (IL-1A) and the -511 C/T polymorphism of the interleukin 1B gene (IL-1B) on the extent of neuroinflammation in the brain in Alzheimer's disease (AD), as demonstrated by the degree of microglial cell activity associated with each IL-1A and IL-1B genotype. METHOD: Microglial cell activity within the frontal cortex was determined in 68 patients with necropsy confirmed AD by image analysis as the percentage area of tissue occupied by ferritin immunostained material (microglial cell load). IL-1A, IL-1B, and apolipoprotein E (APOE) genotyping were performed by polymerase chain reaction on DNA extracted from frontal cortex or cerebellum. RESULTS: The microglial cell load was 31% greater in patients with IL-1A T allele, 62% greater with IL-1A TT genotype, but 108% greater with IL-1A TT genotype in combination with APOE epsilon4 allele. No effects on microglial cell load occurred with polymorphisms in IL-1B, or APOE alone. CONCLUSIONS: Polymorphisms within IL-1A influence the degree of brain microglial cell activation, especially in bearers of APOE epsilon4 allele, reinforcing the importance of neuroinflammatory processes in the pathogenesis of AD, and supporting the rationale for treating the disease with inflammation modulating drugs.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Interleukin-1/genetics , Microglia/cytology , Microglia/physiology , Polymorphism, Genetic , Adult , Age of Onset , Aged , Aged, 80 and over , Apolipoproteins E/genetics , Autopsy , Cell Division , Female , Genotype , Humans , Male , Middle AgedABSTRACT
Polymorphisms in the interleukin-1 genes, IL-1A and IL-1B, have been associated with AD, but not in all studies. The authors genotyped the IL-1A(-889) and IL-1B(-511) polymorphisms in large independent cohorts of 503 control individuals and 395 patients with AD, and a further 100 with brain Abeta load. No evidence was found of risk for AD with these variants, nor of an effect on age at onset. However, an impact of IL-1B(-511) on Abeta(40) load (p < 0.05) was detected.
Subject(s)
Alzheimer Disease/genetics , Interleukin-1/genetics , Polymorphism, Genetic/genetics , Adult , Age of Onset , Aged , Aged, 80 and over , Analysis of Variance , Chi-Square Distribution , Cohort Studies , Female , Gene Frequency/genetics , Genotype , Humans , Male , Middle Aged , Risk FactorsABSTRACT
Darier's disease is a rare autosomal dominantly inherited keratosis.(1) We have previously reported a family in which major affective disorder co-segregated with Darier's disease, consistent with linkage between the Darier gene and a susceptibility locus for affective illness (max lod = 2.1).(2) The Darier gene has been mapped to 12q 23-q24.1 and identified as ATP2A2, a gene encoding SERCA2-a sarcoplasmic/endoplasmic reticulum calcium pump that plays a role in intracellular calcium signalling.(3) A number of groups have reported independent evidence of linkage between bipolar disorder and markers in this region.(4) We here describe a further Caucasian family of European origin in which there is co-occurrence of Darier's disease and major affective disorder including bipolar disorder and report the results of linkage analysis employing genetic markers flanking the Darier's gene. The pedigree includes two individuals with mood disorder from a branch of the family not affected with Darier's disease. However, there is a new mutation in the Darier (ATP2A2) gene in this family and all individuals affected by mood disorder show co-segregation with a haplotype in the region of the Darier's gene (max lod = 3.58). The family provides strong evidence against the Darier-causing mutation itself playing a major role in affective disorder but strongly supports the existence of a bipolar disorder susceptibility gene in the Darier region.
Subject(s)
Bipolar Disorder/genetics , Darier Disease/genetics , Family Health , Genetic Linkage , Calcium-Transporting ATPases/genetics , Female , Genetic Markers , Genetic Predisposition to Disease , Humans , Male , Pedigree , Sarcoplasmic Reticulum Calcium-Transporting ATPasesABSTRACT
There are numerous polymorphisms within the tau gene but these are in complete linkage disequilibrium and exist as two common extended haplotypes H1 and H2. We have investigated the frequency of these haplotypes in 83 cases of sporadic Alzheimer's disease (AD) using the +34 polymorphism in intron 11 of the tau gene as a marker of H1 and H2 haplotypes. The total amount of hyperphosphorylated tau protein (tau load), present as neurofibrillary tangles, neuropil threads or plaque neurites, was quantified in the frontal cortex of these patients and related to tau haplotype. We found no increase in H1H1 haplotype in this autopsy population of cases with AD compared to published control data. Stratification of cases for apolipoprotein E (APO E) genotype showed a slight, but not statistically significant, overrepresentation of epsilon 4 allele amongst bearers of H2 haplotype. There were no overall differences in tau load between haplotype groups though cases within each haplotype group bearing APO E epsilon 4 allele had a significantly higher tau load than those without epsilon 4 allele. Neither age at onset or duration of illness differed according to tau haplotype. We conclude that the frequency of tau gene H1 haplotype is not elevated in AD and possession of this has no impact upon the amount of tau pathology in AD.