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1.
Am J Hum Genet ; 105(4): 706-718, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564435

RESUMO

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

2.
Sci Rep ; 9(1): 1800, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755687

RESUMO

Genome-Wide Association (GWA) with population-based imputation (PBI) has been successful in identifying common variants associated with complex diseases; however, much heritability remains to be explained and low frequency variants (LFV) may contribute. To identify LFV, a study of unrelated individuals may no longer be as efficient as a family study, where rare population variants can be frequent in families. Family-based imputation (FBI) provides an opportunity to evaluate LFV. To compare the performance of PBI and FBI, we conducted extensive simulations, generating genotypes using SeqSIMLA from various reference panels for families. We masked genotype information for variants unavailable in Framingham 550 K GWA genotype data in less informative subjects selected by GIGI-Pick. We implemented IMPUTE2 with duoHMM in SHAPEIT (Impute2_duoHMM) for PBI, MERLIN and GIGI for FBI and PedBLIMP for a hybrid approach. In general, FBI in both MERLIN and GIGI outperformed other approaches with imputation accuracy greater than 0.99 for the squared correlation and imputation quality scores (IQS) especially for LFV, although imputation accuracy from MERLIN depends on pedigree splitting for larger families. PBI performed worst with the exception of good imputation accuracy for common variants when a closely ancestry matched reference is used. In summary, linkage disequilibrium (LD) information from large available genotype resources provides good imputation for common variants with well-selected reference panels without requiring densely sequenced data in family members, while imputation of LFV with FBI benefits more from information on inheritance patterns within families yielding better imputation.

3.
Am J Hum Genet ; 104(2): 260-274, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639324

RESUMO

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.

4.
Hum Genet ; 138(2): 199-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30671673

RESUMO

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.


Assuntos
Pressão Sanguínea/genética , Cromossomos Humanos Par 16/genética , Exoma , Ligação Genética , Variação Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Processamento Alternativo/genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores de Processamento de RNA/genética , Recombinases/genética
5.
Genet Epidemiol ; 43(3): 263-275, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30653739

RESUMO

When testing genotype-phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse consequences for rarer variants. Because genotypes are expected to have small effects (if any) investigators now routinely use a two-stage method, in which they first regress the trait on covariates, obtain residuals, rank-normalize them, and then use the rank-normalized residuals in association analysis with the genotypes. Potential confounding signals are assumed to be removed at the first stage, so in practice, no further adjustment is done in the second stage. Here, we show that this widely used approach can lead to tests with undesirable statistical properties, due to both combination of a mis-specified mean-variance relationship and remaining covariate associations between the rank-normalized residuals and genotypes. We demonstrate these properties theoretically, and also in applications to genome-wide and whole-genome sequencing association studies. We further propose and evaluate an alternative fully adjusted two-stage approach that adjusts for covariates both when residuals are obtained and in the subsequent association test. This method can reduce excess Type I errors and improve statistical power.


Assuntos
Estudos de Associação Genética , Modelos Genéticos , Simulação por Computador , Estudo de Associação Genômica Ampla , Genótipo , Hemoglobinas/metabolismo , Hispano-Americanos , Humanos , Modelos Lineares , Fenótipo
6.
Int J Obes (Lond) ; 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232418

RESUMO

OBJECTIVE: Indices of body fat distribution are heritable, but few genetic signals have been reported from genome-wide association studies (GWAS) of computed tomography (CT) imaging measurements of body fat distribution. We aimed to identify genes associated with adiposity traits and the key drivers that are central to adipose regulatory networks. SUBJECTS: We analyzed gene transcript expression data in blood from participants in the Framingham Heart Study, a large community-based cohort (n up to 4303), as well as implemented an integrative analysis of these data and existing biological information. RESULTS: Our association analyses identified unique and common gene expression signatures across several adiposity traits, including body mass index, waist-hip ratio, waist circumference, and CT-measured indices, including volume and quality of visceral and subcutaneous adipose tissues. We identified six enriched KEGG pathways and two co-expression modules for further exploration of adipose regulatory networks. The integrative analysis revealed four gene sets (Apoptosis, p53 signaling pathway, Proteasome, Ubiquitin-mediated proteolysis) and two co-expression modules with significant genetic variants and 94 key drivers/genes whose local networks were enriched with adiposity-associated genes, suggesting that these enriched pathways or modules have genetic effects on adiposity. Most identified key driver genes are involved in essential biological processes such as controlling cell cycle, DNA repair, and degradation of regulatory proteins are cancer related. CONCLUSIONS: Our integrative analysis of genetic, transcriptional, and biological information provides a list of compelling candidates for further follow-up functional studies to uncover the biological mechanisms underlying obesity. These candidates highlight the value of examining CT-derived and central adiposity traits.

7.
BMC Genet ; 19(Suppl 1): 70, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30255765

RESUMO

BACKGROUND: In studies with multi-omics data available, there is an opportunity to investigate interdependent mechanisms of biological causality. The GAW20 data set includes both DNA genotype and methylation measures before and after fenofibrate treatment. Using change in triglyceride (TG) levels pre- to posttreatment as outcome, we present a mediation analysis that incorporates methylation. This approach allows us to simultaneously consider a mediation hypothesis that genotype affects change in TG level by means of its effect on methylation, and an interaction hypothesis that the effect of change in methylation on change in TG levels differs by genotype. We select 322 single-nucleotide polymorphism-cytosine-phosphate-guanine (SNP-CpG) site pairs for mediation analysis on the basis of proximity and marginal genome-wide association study (GWAS) and epigenome-wide association study (EWAS) significance, and present results from the real-data sample of 407 individuals with complete genotype, methylation, TG levels, and covariate data. RESULTS: We identified 3 SNP-CpG site pairs with significant interaction effects at a Bonferroni-corrected significance threshold of 1.55E-4. None of the analyzed sites showed significant evidence of mediation. Power analysis by simulation showed that a sample size of at least 19,500 is needed to detect nominally significant indirect effects with true effect sizes equal to the point estimates at the locus with strongest evidence of mediation. CONCLUSIONS: These results suggest that there is stronger evidence for interaction between genotype and methylation on change in triglycerides than for methylation mediating the effect of genotype.

8.
Mol Psychiatry ; 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30108311

RESUMO

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10-7), an immunoglobulin gene whose antibodies interact with ß-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10-7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10-6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

9.
Nat Commun ; 9(1): 3391, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30140000

RESUMO

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

11.
Nat Commun ; 9(1): 2606, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973585

RESUMO

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

12.
Eur J Hum Genet ; 26(9): 1369-1377, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29967334

RESUMO

A recent genome-wide association study (GWAS) of central obesity identified 27 loci, from sex-combined analysis, associated with waist-to-hip ratio adjusted for body-mass index (WHRadjBMI) in European-ancestry individuals. Nevertheless, the identified variants may not be the biological causal ones due to the presence of linkage disequilibrium (LD). To better understand the mechanisms underlying the identified loci from the GWAS meta-analysis, we first imputed summary statistics at GWAS loci to increase genetic resolution, and then we applied a Bayesian statistical fine-mapping method through PAINTOR, incorporating LD structure and functional annotations to select and prioritize the most plausible causal variants across WHRadjBMI-associated regions. Using adipose tissue- and cell-specific annotations that showed significant associations with WHRadjBMI, we identified 33 single-nucleotide polymorphisms (SNPs) from 27 sex-combined fine-mapping loci with posterior probability of causality greater than 0.9. Six of the selected 33 SNPs belong to at least one of the top five identified annotations. SNPs rs1440372 (SMAD6) and rs12608504 (JUND) are particularly important since they not only have associated functional annotations but are also GWA hits in the original study. Incorporation of functional annotations helps identify additional plausible causal variants, such as rs2213731 (DNM3-PIGC) and rs4531856 (JUND), that did not reach genome-wide significance in GWAS. Our results provide promising candidates for future functional validation experiments.

13.
Circ Genom Precis Med ; 11(5): e001663, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29752399

RESUMO

BACKGROUND: Genetic variants at the SCN5A/SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. METHODS: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (r 2=0.86) with each other to be the strongest signals for PR (rs10428132, ß=-4.74, P=1.52×10-14) and QRS intervals (rs6599251, QRS ß=-0.73; P=1.2×10-4), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium (r 2≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P=0.03, and I962V+V1073A, 22.4±0.8%, P=0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P=0.03). CONCLUSIONS: Our findings suggest an association between genetic variation in SCN10A, the late sodium current, and alterations in cardiac conduction.

14.
Spine J ; 2018 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-29679729

RESUMO

BACKGROUND CONTEXT: Prevalence and progression of disc height narrowing (DHN) and facet joint osteoarthritis (FJOA) in the thoracic and lumbar regions in non-clinical populations are not well established. PURPOSE: The present study aimed to use computed tomography (CT) images to determine the prevalence and progression of DHN and FJOA according to age, sex, and spinal region. STUDY DESIGN: This is a 6-year longitudinal study. SAMPLE: A total of 1,195 members of the Framingham Study (mean baseline age 61±9 years) were included in the study. OUTCOME MEASURES: We compared the prevalence and progression (new or worsening) of moderate-to-severe DHN and FJOA by age, sex, and spinal region. METHODS: A musculoskeletal radiologist evaluated DHN and FJOA from T4/T5 to L4/L5 on baseline and follow-up CT images using a semi-quantitative scale: 0=normal, 1=mild, 2=moderate, and 3=severe. RESULTS: One-third or more of women and men ages 40-59 years at baseline had imaged-based evidence of prevalent DHN, more than half had prevalent FJOA, and DHN and FJOA prevalence increased approximately two- to fourfold in those age 60-69 and 70-89 years at baseline, respectively (p<.01). Progression of DHN and FJOA occurred more frequently at the lumbar than at the thoracic spine and more in women than in men (DHN: odds ratio [OR]=1.42, 95% confidence interval [CI]=1.07, 1.88; FJOA: OR=1.70, CI=1.33, 2.17). CONCLUSIONS: Prevalence and progression of moderate-to-severe DHN and FJOA are common in non-clinical populations of older adults. The high frequency of spinal degeneration observed on CTs in this community-based study may contribute to challenges in interpreting the clinical significance of imaging evidence of DHN and FJOA. Future studies investigating the association of CT-based spinal degenerative features with pain and functional impairments in population-based samples are needed to help determine the clinical significance of imaged-based findings of DHN and FJOA.

15.
PLoS Genet ; 14(4): e1007222, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29608557

RESUMO

Human GWAS of obesity have been successful in identifying loci associated with adiposity, but for the most part, these are non-coding SNPs whose function, or even whose gene of action, is unknown. To help identify the genes on which these human BMI loci may be operating, we conducted a high throughput screen in Drosophila melanogaster. Starting with 78 BMI loci from two recently published GWAS meta-analyses, we identified fly orthologs of all nearby genes (± 250KB). We crossed RNAi knockdown lines of each gene with flies containing tissue-specific drivers to knock down (KD) the expression of the genes only in the brain and the fat body. We then raised the flies on a control diet and compared the amount of fat/triglyceride in the tissue-specific KD group compared to the driver-only control flies. 16 of the 78 BMI GWAS loci could not be screened with this approach, as no gene in the 500-kb region had a fly ortholog. Of the remaining 62 GWAS loci testable in the fly, we found a significant fat phenotype in the KD flies for at least one gene for 26 loci (42%) even after correcting for multiple comparisons. By contrast, the rate of significant fat phenotypes in RNAi KD found in a recent genome-wide Drosophila screen (Pospisilik et al. (2010) is ~5%. More interestingly, for 10 of the 26 positive regions, we found that the nearest gene was not the one that showed a significant phenotype in the fly. Specifically, our screen suggests that for the 10 human BMI SNPs rs11057405, rs205262, rs9925964, rs9914578, rs2287019, rs11688816, rs13107325, rs7164727, rs17724992, and rs299412, the functional genes may NOT be the nearest ones (CLIP1, C6orf106, KAT8, SMG6, QPCTL, EHBP1, SLC39A8, ADPGK /ADPGK-AS1, PGPEP1, KCTD15, respectively), but instead, the specific nearby cis genes are the functional target (namely: ZCCHC8, VPS33A, RSRC2; SPDEF, NUDT3; PAGR1; SETD1, VKORC1; SGSM2, SRR; VASP, SIX5; OTX1; BANK1; ARIH1; ELL; CHST8, respectively). The study also suggests further functional experiments to elucidate mechanism of action for genes evolutionarily conserved for fat storage.


Assuntos
Índice de Massa Corporal , Cruzamentos Genéticos , Drosophila melanogaster/genética , Estudo de Associação Genômica Ampla , Obesidade/genética , Interferência de RNA , Tecido Adiposo , Animais , Humanos , Camundongos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
16.
Artigo em Inglês | MEDLINE | ID: mdl-29688268

RESUMO

Background: Cross-sectional studies suggest that trunk muscle morphology in the lumbar spine is an important determinant of kyphosis severity in older adults. The contribution of age-related changes in muscle morphology in the thoracic and lumbar spine to progression of kyphosis is not known. Our objective was to determine cross-sectional and longitudinal associations of thoracic and lumbar muscle size and density with kyphosis. Methods: Participants were 1,087 women and men (mean age 61y) of the Framingham Heart Study who underwent baseline and follow-up quantitative computed tomography (QCT) scanning 6y apart. We used QCT scans to measure trunk muscle cross-sectional area (CSA, cm2) and density (HU) at the thoracic and lumbar spine and Cobb angle (degrees) from T4 to T12. Linear regression models estimated the association between muscle morphology and kyphosis. Results: At baseline, smaller muscle CSA and lower density of thoracic (but not lumbar) spine muscles were associated with a larger (worse) Cobb angle in women and men. For example, each standard deviation (SD) decrease in baseline thoracic paraspinal muscle CSA was associated with a larger baseline Cobb angle in women (3.7°, 95%CI:2.9, 4.5) and men (2.5°, 95%CI:1.6, 3.3). Longitudinal analyses showed that loss of muscle CSA and density at the thoracic and lumbar spine was not associated with progression of kyphosis. Conclusion: Our findings suggest that kyphosis severity is related to smaller and lower density trunk muscles at the thoracic spine. Future studies are needed to determine how strengthening mid-back musculature alters muscle properties and contributes to preventing kyphosis progression.

17.
Nat Commun ; 9(1): 260, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343764

RESUMO

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

18.
Calcif Tissue Int ; 103(1): 16-23, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29305636

RESUMO

Although muscle mass influences strength in older adults, it is unclear whether low lean mass measured by dual-energy X-ray absorptiometry (DXA) is an independent risk factor for hip fracture. Our objective was to determine the association between DXA lean mass and incident hip fracture risk among 1978 women aged 50 years and older participating in the Framingham Study Original and Offspring cohorts. Leg and total body lean mass (kg) were assessed from whole-body DXA scans collected in 1992-2001. Hip fracture follow-up extended from DXA assessment to the occurrence of fracture, death, drop-out, or end of follow-up in 2007. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) estimating the relative risk of hip fracture associated with a 1-kg increase in baseline lean mass. Mean age was 66 years (range 50-93). Over a median of 8 years of follow-up, 99 hip fractures occurred. In models adjusted for age, height, study cohort, and percent total body fat, neither leg (HR 1.11; 95% CI 0.94, 1.31) nor total body (HR 1.06; 95% CI 0.99, 1.13) lean mass were associated with hip fracture. After further adjustment for femoral neck bone mineral density, leg lean mass results were similar (HR 1.10; 95% CI 0.93, 1.30). In contrast, 1 kg greater total body lean mass was associated with 9% higher hip fracture risk (HR 1.09; 95% CI 1.02, 1.18). Our findings suggest that in women, lower lean mass measured by DXA is not associated with increased risk of hip fracture.

19.
Genet Med ; 20(1): 132-141, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28726810

RESUMO

PurposeTelephone disclosure of genetic test results can improve access to services. To date, studies of its impact have focused on return of Mendelian risk information, principally hereditary cancer syndromes.MethodsIn a multisite trial of Alzheimer disease genetic risk disclosure, asymptomatic adults were randomized to receive test results in person or via telephone. Primary analyses examined patient outcomes 12 months after disclosure.ResultsData from 257 participants showed that telephone disclosure occurred 7.4 days sooner and was 30% shorter, on average, than in-person disclosure (both P < 0.001). Anxiety and depression scores were well below cutoffs for clinical concern across protocols. Comparing telephone and in-person disclosure protocols, 99% confidence intervals of mean differences were within noninferiority margins on scales assessing anxiety, depression, and test-related distress, but inconclusive about positive impact. No differences were observed on measures of recall and subjective impact. Subanalyses supported noninferiority on all outcomes among apolipoprotein E (APOE) ɛ4-negative participants. Subanalyses were inconclusive for APOE ɛ4-positive participants, although mean anxiety and depression scores were still well below cutoffs for clinical concern.ConclusionTelephone disclosure of APOE results and risk for Alzheimer disease is generally safe and helps providers meet demands for services, even when results identify an increased risk for disease.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Revelação , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Telefone , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Adulto Jovem
20.
Neurology ; 90(3): e188-e196, 2018 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-29282330

RESUMO

OBJECTIVE: We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program. METHODS: We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants. RESULTS: We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10-4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10-3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways. CONCLUSIONS: Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.

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