A novel Alzheimer disease locus located near the gene encoding tau protein.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus.

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

Involvement of hormonal circadian secretion in the growth of HIV-infected children.

OBJECTIVE: To evaluate the circadian secretion of hormones involved in the regulation of growth in childhood, namely growth hormone, insulin-like growth factor (IGF)-I, cortisol, adrenocorticotropin hormone (ACTH), and thyroid-stimulating hormone (TSH) in HIV-infected children. DESIGN: The circadian secretory pattern of growth hormone, IGF-I, cortisol, ACTH and TSH was evaluated in 14 HIV-infected children; 13 healthy age- and sex-matched children were chosen as controls. METHODS: Sampling was performed every 4 h from 0400 h to 2000 h and every 2 h from 2000 h to 0400 h. Rhythmometric data were analysed by single and population mean cosinor methods and by analysis of variance. RESULTS: A statistically significant circadian rhythm for growth hormone, IGF-I and cortisol was detectable in HIV-seropositive children, but the mean basal IGF-I levels were below the normal range for age in 12 patients. A statistically significant circadian rhythm was not detectable for ACTH or TSH. CONCLUSION: These results show that there is a loss of the physiological regulation of growth hormone-IGF-I axis and a modification of 24 h TSH profile in our HIV-infected children. These abnormalities might be involved in the altered growth mechanism leading to the failure to thrive that is a peculiar feature of HIV-infected children.

Evidence for linkage between essential hypertension and a putative locus on human chromosome 17.

Several clinical and animal studies indicate that essential hypertension is inherited as a multifactorial trait with a significant genetic and environmental component. In the stroke-prone spontaneously hypertensive rat model, investigators have found evidence for linkage to blood pressure regulatory genes (quantitative trait loci) on rat chromosomes 2, 10, and X. In 1 human study of French and UK sib pairs, evidence for linkage has been reported to human chromosome 17q, the syntenic region of the rat chromosome 10 quantitative trait loci (QTL). Our study confirms this linkage (P=0.0005) and refines the location of the blood pressure QTL.

Genome-wide scan for Parkinson's disease: the GenePD Study.

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Familial paragangliomas: linkage to chromosome 11q23 and clinical implications.

Familial paragangliomas (PGL), or glomus tumors, are slow-growing, highly vascular, generally benign neoplasms usually of the head and neck that arise from neural crest cells. This rare autosomal-dominant disorder is highly penetrant and influenced by genomic imprinting through paternal transmission. Timely detection of these tumors affords the affected individual the opportunity to avoid the potential morbidity associated with surgical removal, and mortality that may accompany local and distant metastases. Linkage to two distinct chromosomal loci, 11q13.1 and 11q22.3-q23, has been reported, suggesting heterogeneity. We evaluated three multigenerational families with hereditary PGL, including 19 affected, and 59 unaffected and potentially at-risk individuals. Numerous microsatellite markers corresponding to each candidate region were tested in all members of the three families. Confirmation of linkage to 11q23 was established in all three families. The inheritance pattern was consistent with genetic imprinting. Using these data, we were able to provide presymptomatic diagnosis with subsequent removal of tumor from one individual, and to start several others on an MRI surveillance protocol.

Identification of a polymorphic glutamic acid stretch in the alpha2B-adrenergic receptor and lack of linkage with essential hypertension.

Essential hypertension, a clinically significant elevation in blood pressure with no recognizable cause, is believed to be attributable to the collective effect of genetic predisposing factors in combination with specific environmental factors, such as diet and stress. Of the genetic causes, genes coding for proteins involved in blood pressure regulation, such as the alpha- and beta-adrenergic receptors, are obvious candidates. The alpha2-adrenergic receptor plays a key role in the sympathetic nervous system by mediating the effects of epinephrine and norepinephrine. To evaluate the potential role between the alpha2B receptor and essential hypertension, we scanned the alpha2B-receptor gene for genetic variation in 108 affected sibling pairs. The screening revealed two major forms of the receptor. They differ by the presence of either 9 or 12 glutamic acid residues in the acidic domain of the third cytoplasmic loop of the protein. Investigation of the pattern of this variation in hypertensive sibling pairs suggests that the alpha2B receptor locus does not contribute substantially to genetic susceptibility for essential hypertension.

Haplotypes and gene expression implicate the MAPT region for Parkinson disease: the GenePD Study.

BACKGROUND: Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum. METHODS: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. RESULTS: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT. CONCLUSIONS: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.

Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study.

BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Absence of previously reported variants in the SCNA (G88C and G209A), NR4A2 (T291D and T245G) and the DJ-1 (T497C) genes in familial Parkinson's disease from the GenePD study.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

The effect of alpha 2 macroglobulin-proteinase complexes on macrophage Ia expression in vivo.

Alpha-2-Macroglobulin (alpha 2M) is a major plasma proteinase inhibitor. It can also regulate the function of cells of the immune system, including macrophage expression of Ia antigens in tissue culture systems. The present work was done to assess the effect of alpha 2M-trypsin complexes (alpha 2M-t) on macrophage Ia expression in vivo. Bacillus Calmette-Guerin-infected mice were injected intraperitoneally with 100nM alpha 2M-t, phosphate buffered saline (PBS), or bovine serum albumin (BSA) in PBS. The peritoneal cells were harvested by lavage from 3 to 6 days after injection. Differential cell counts were performed, and macrophage Ia antigen expression determined by indirect immunofluorescence. Injection of either alpha 2M-t or BSA solutions tended to increase the number of total cells and lymphocytes harvested, without changing the number of macrophages harvested. alpha 2M-t injection reduced the proportion of macrophages which were Ia positive from 60 to 37% on day 3 after injection, and to 20% Ia positive on day 6. The reduction in Ia positive macrophages was statistically significant when compared to either PBS or BSA injected groups. In summary, in vivo exposure to alpha 2M-t can alter macrophage function. alpha 2M-proteinase complexes formed during the course of coagulation or inflammation may play a physiologic role as regulators of the immune response.

Heritability estimates of transformations of normally distributed records.

Milk yields were simulated for identical twin and parent-progeny pairs to determine effect of transformations on genetic variance. Use of identical twin pairs excludes variability due to Mendelian sampling and contribution by the other parent present in parent-progeny records. Phenotypic variances of 616,800; 1,439,200; and 2,261,600 and means from 2267 to 13,603 by increments of 2267 were used for linear scale records. Phenotypic variances of .01000, .01875, and .02750 and means equal to the natural logarithm of the means for linear scale were used for log scale records. Heritability varied from .05 to .95 by increments of .10. For each combination of parameters, 10 replicates of 10,000 pairs of relatives were created. Data normally distributed on a linear scale were log transformed. Log normally distributed data were exponentially transformed. Heritability estimates from correlations among relatives indicated heritability is larger for normally distributed data than for transformed data. For parent-progeny pairs, the difference increased as heritability increased, and for identical twin pairs, the differences were least at extremely large and small heritabilities. For both types of relative pairs, the difference increased as phenotypic variance increased. Absolute differences in heritability ranged from .0000 to .0089, a difference of little practical importance.

Life satisfaction and coping of diabetic hemodialysis patients.

End-stage diabetic patients who are dependent on hemodialysis live with multiple deficits and discomforts. Their quality of life would seem dismal to others. The perceptions of the patients themselves, however, might be quite different. In this descriptive study, 12 such patients were interviewed using Cantril's Self-Anchoring Striving Scale. The mean satisfaction rating for the anticipated future was almost as high as the past, despite experiencing a long-standing downward health spiral. Content analysis of the interviews suggested coping patterns of people who are living with a chronic disease.

Magnesium potentiates imipramine toxicity in the isolated rat heart.

STUDY OBJECTIVE: To study the effect of magnesium on cardiac function and hemodynamics during imipramine toxicity. DESIGN: After stabilization, isolated, beating rat hearts were perfused with Krebs-Henseleit bicarbonate buffer (KHB) solution containing 2.0 mg/L imipramine (IMIP) and 2.4 mEq [Mg2+] until toxicity, defined as 25% widening of the ventricular depolarization duration (VDD). Experiments were performed at either constant coronary perfusion pressure or flow. SETTING: Animal research laboratory of a large, urban hospital. MEASUREMENTS: Heart rate, VDD, left ventricular pressure and +/- dP/dt, and coronary flow. INTERVENTIONS: On onset of toxicity, KHB+IMIP was switched to either control (KHB+IMIP), magnesium (KHB+IMIP+4.0 or 6.0 mEq/L [Mg2+]), or hypertonic alkaline treatment (165 mEq/L [Na+], pH 7.55). RESULTS: At a constant coronary perfusion pressure of 100 mm Hg, magnesium at 6.0 mEq produced significant decreases in heart rate, left ventricular pressure, +dP/dt, and increase in VDD versus control. With coronary flow held constant, magnesium reduced left ventricular pressure and +dP/dt but not heart rate or VDD. Incidences of electromechanical dissociation and asystole were higher with magnesium versus control. Hypertonic alkaline treatment tended to improve all parameters in constant pressure and constant flow experiments. CONCLUSION: Magnesium potentiates IMIP-induced negative inotropic effects and cardiac conduction defects in isolated rat hearts.

A novel mutation in the MITF gene causes Waardenburg syndrome type 2.

Mutations in the MITF gene on human chromosome 3 have been reported in families with Waardenburg Syndrome Type 2 (WS2), an autosomal dominant disorder responsible for a large proportion of congenital hearing loss. We examined 16 families with WS2 for mutations in the MITF gene. In one four-generation family, we found a novel two-base deletion in exon 6 of the MITF gene at nucleotide position 699. This mutation introduces a frame-shift and stop codon which leads to a truncation of the protein. This mutation is predicted to have phenotypic consequences not withstanding evidence of reduced penetrance and heterogeneity within the family studied.