Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an ...early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.
Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging ...cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.
We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m
to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.
We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (
=3.0×10
), lies upstream of
, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within
and upstream of
(a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within
, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.
Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.
We compared oculomotor control among individuals in the early stages of Huntington’s disease (HD), with that of individuals who are presymptomatic HD gene carriers (PSGC) and nongene carriers (NGC). ...The oculomotor testing paradigm included both traditional tests and a novel experimental procedure to assess visual scanning. Traditional tests elicited saccades, pursuit and optokinetic nystagmus (OKN). HD patients demonstrated marked delay in the initiation of volitional saccades (anti-saccade and memory-guided saccades), a reduced number of correct volitional saccades, reduced velocity of saccades, and a decreased OKN gain. We also studied visual scanning while the participants completed the Digit Symbol Subscale of the Wechsler Adult Intelligence Survey-Revised (WAIS-R). The HD participants demonstrated an abnormal gaze strategy, which may be associated with attention and/or planning deficits.
Differences between the PSGC and NGC groups were only observed for two measures: PSGC had a decreased number of memory-guided saccades and a subtle delay in the initiation of volitional saccades. Our results suggest that oculomotor measures are a sensitive biomarker in the early stage of HD and demonstrate that the combination of more traditional oculomotor tests with visual scanning tests is useful in the evaluation of visual performance.
Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an ...integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.
Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 ...cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.
External apical root resorption (EARR) is a common orthodontic treatment sequela.
Previous studies implicate a substantial genetic component for EARR. Using a
candidate gene approach, we investigated ...possible linkage of EARR associated with
orthodontic treatment with the TNSALP, TNF
α
, and TNFRSF11A gene
loci. The sample was comprised of 38 American Caucasian families with a total of 79
siblings who completed comprehensive orthodontic treatment. EARR was assessed by
means of pre- and post-treatment radiographs. Buccal swab cells were collected for
extraction and analysis of DNA. No evidence of linkage was found with EARR and the
TNF
α and TNSALP genes.
Non-parametric sibling pair linkage analysis identified evidence of linkage (LOD =
2.5; p = 0.02) of EARR affecting the maxillary central incisor with the
microsatellite marker D18S64 (tightly linked to TNFRSF11A). This indicates that the TNFRSF11A locus, or another tightly linked gene, is associated with
EARR.
The genetic basis of familial primary pulmonary hypertension (FPPH) is unknown, but the clinical and pathologic features are the same as in sporadically occurring primary pulmonary hypertension ...(PPH). Because few families with this disease have been reported, the mode of inheritance and genetic features have not been clearly established. We previously reported a tendency for decreasing age of onset in subsequent generations of affected families. The purpose of this study was to examine the pattern of inheritance in a large number of families in an attempt to find clues to pathogenesis. From 24 families we studied 429 members, 124 of whom were known to carry the gene for disease. We constructed cumulative mortality curves for each gender of the 99 affected individuals. We analyzed gender ratios of progeny of affected members and carriers and compared age at death of affected members by generation. More females (160) than males (122) were born to persons carrying the gene, p < 0.01, suggesting selective wastage of male fetuses or an abnormal primary sex ratio. Genetic anticipation was confirmed; the age at death was 45.6 +/- 14.5 versus 36.3 +/- 12.6 versus 24.2 +/- 11 standard deviation (SD) years in successive generations, p < 0.05. Five cases of male-to-male transmission were observed, excluding X-linkage. Age at death was the same for males and females. More females had the gene (84 females, 40 males) and more females with the gene developed disease (72 of 84 females 86% versus 27 of 40 males 68%). The disease has highly variable penetrance among families.
The Alox15 gene was recently identified as a negative regulator of peak BMD in mice. Polymorphisms in human ALOX12, but not ALOX15, were significantly associated with spine BMD in white men and ...women, suggesting that ALOX12 may contribute to normal variation in BMD.
Introduction: Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporosis is peak BMD, which is a highly heritable trait. Recently, the arachidonate 15‐lipoxygenase (Alox15) gene was identified as a negative regulator of peak BMD in mice.
Materials and Methods: To assess the contribution of lipoxygenase genes to normal BMD variation in healthy white men and women, we performed population‐ and family‐based association studies of two arachidonate lipoxygenase genes: ALOX15, which is the human homolog of mouse Alox15, and ALOX12, which is functionally similar to Alox15. Single nucleotide polymorphisms (SNPs) distributed across the two genes were genotyped. BMD was measured at the femoral neck and lumbar spine in 411 men 18–61 years of age and 1291 premenopausal women 20–50 years of age.
Results: Moderate evidence of association was found between spine BMD and six SNPs in the ALOX12 gene in both men and women (p = 0.0052–0.050). Furthermore, the most common SNP haplotype in ALOX12 showed evidence of significant association with high spine BMD in men (p = 0.0083), whereas the second most common haplotype was associated with high spine BMD in women (p = 0.0081).
Conclusions: Polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.
Fetal alcohol syndrome (FAS) is particularly common among the mixed-ancestry population of the Western Cape Province of South Africa and occurs at a frequency of 0.0392-0.0429 (39.2-42.9 of 1000) ...among 5- to 9-year-old school entrants. While FAS is clearly caused by an environmental insult, studies in twins and mice support a significant genetic contribution to risk for FAS. It is likely that the development of FAS following excessive alcohol exposure is influenced by genetic factors in both the mother and the child. Known polymorphisms of the alcohol dehydrogenase-2 (ADH2) gene resulting in isozymes with different alcohol oxidizing capacities were investigated as possible candidates for influencing the risk for FAS.
Genotyping was undertaken for the ADH2 locus in 56 FAS-affected children, their 56 mothers, and 178 control individuals of mixed ancestry from the same geographic region. The ADH2 alleles were analyzed for the three groups and the allele frequencies of the mother and FAS-affected children were independently compared with the control group.
The ADH2*2 allele was found to be significantly more common in the control group than in the mothers of FAS-affected children (p = 0.025 +/- 0.004) and in the FAS subjects (p = 0.025 +/- 0.004). The ADH2*3 allele frequency was low and was not significantly different between the groups.
The ADH2*2 allele is significantly more common in control individuals, suggesting that it may either confer protection or be a marker for a protective effect against FAS among individuals of mixed ancestry in the Western Cape Province of South Africa.
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