Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms ...(SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility. Each family has at least one avuncular or cousin pair with ASD. Families were then evaluated for co-segregation of CNVs in ASD patients. We identified a total of five deletions and seven duplications in eleven families that co-segregated with ASD. Two of the CNVs overlap with regions on 7p21.3 and 15q24.1 that have been previously reported in ASD individuals and two additional CNVs on 3p26.3 and 12q24.32 occur near regions associated with schizophrenia. These findings provide further evidence for the involvement of ICA1 and NXPH1 on 7p21.3 in ASD susceptibility and highlight novel ASD candidates, including CHL1, FGFBP3 and POUF41. These studies highlight the power of using extended families for gene discovery in traits with a complex etiology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prior studies have demonstrated that microglial activation is involved in the pathogenesis of primary open-angle glaucoma (POAG). Here we sought to identify genetic associations between POAG and ...variants in APOE and TREM2, genes associated with Alzheimer disease (AD) that critically regulate microglial neurodegeneration-associated molecular signature.
APOE genotypes were called using imputed data from the NEIGHBOR consortium (2120 POAG cases, 2262 controls) and a second cohort from the Massachusetts Eye and Ear Infirmary (MEEI; 486 cases, 344 controls). TREM2 coding variants were genotyped by means of the Illumina HumanExome BeadArray. The data set was analyzed for association with POAG overall, as well as the high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) subgroups, using logistic regression adjusting for age and sex.
In the combined NEIGHBOR-MEEI data set, significant association was observed for APOE ε4 in POAG overall (odds ratio OR, 0.83; 95% confidence interval CI, 0.74-0.94; P = 0.0022) and in both the HTG subgroup (OR, 0.81; 95% CI, 0.70-0.94; P = 0.0052) and NTG subgroup (OR, 0.71; 95% CI, 0.58-0.87; P = 0.0014). A rare TREM2 variant (A105V) was found only in HTG cases (3 of 2863 cases) and in none of the controls (P = 0.03). Three TREM2 rare variants associated with AD were not significantly associated with POAG (P > 0.05).
We have found that the APOE ε4 allele is associated with a reduced risk of POAG. Interestingly, the same allele is adversely associated with AD, suggesting a mechanistic difference between neurodegenerative diseases of the eye and the brain. TREM2 variants associated with AD did not significantly contribute to POAG risk.
Summary
In the age of high‐density genome‐wide association (GWAS) data, correcting for multiple comparisons is a substantial issue for genetic epidemiological studies. However, the current manuscript ...review process generally requires both stringent correction and independent replication. The result of this stringency is that studies that are published suffer from inflated Type 2 error rates (false negatives), thereby removing many likely real signals from follow‐up. Elimination of these alleles, if they are truly associated, from further study will slow research progress in studies of complex disease. We argue that this method of correction is overly conservative, especially in an age when high‐density follow‐up experiments are possible and reasonably inexpensive.
Primary open-angle glaucoma (POAG) is a genetically complex common disease characterized by progressive optic nerve degeneration that results in irreversible blindness. Recently, a genome-wide ...association study (GWAS) for POAG in an Icelandic population identified significant associations with single nucleotide polymorphisms (SNPs) between the CAV1 and CAV2 genes on chromosome 7q31. In this study, we confirm that the identified SNPs are associated with POAG in our Caucasian US population and that specific haplotypes located in the CAV1/CAV2 intergenic region are associated with the disease. We also present data suggesting that associations with several CAV1/CAV2 SNPs are significant mostly in women.
Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (
APOE
), ...comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs)
jointly
associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond
APOE
, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within
MBLAC1
(chromosome 7, meta-
p
= 1.44 × 10
−9
),
MINK1
(chromosome 17, meta-
p
= 1.98 × 10
−7
) and two chromosome 11 SNPs within the
MTCH2/SPI1
region (closest gene =
DDB2
, meta-
p
= 7.01 × 10
−7
and closest gene =
MYBPC3
, meta-
p
= 5.62 × 10
−8
). In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within
MINK1
,
MBLAC1,
and
DDB2.
Expression of
MBLAC1, SPI1, MINK1
and
DDB2
was differentially altered within postmortem AD brains. Beyond
APOE
, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.
The ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene is associated with Alzheimer’s disease (AD) risk in populations of African, Asian, and European ancestry1-5. Numerous ABCA7 ...mutations contributing to risk have been identified, including a 44 base pair deletion (rs142076058) specific to individuals of African ancestry and predicted to cause a frameshift mutation (p.Arg578Alafs) (Cukier et al., 2016). The UMi043-A human induced pluripotent stem cell line was derived from an African American individual with AD who is heterozygous for this deletion and is a resource to further investigate ABCA7 and how this African-specific deletion may influence disease pathology.
Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ42 are established biomarkers for Alzheimer’s disease (AD) and have been used as quantitative traits for genetic ...analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10−9 for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10−8 and p = 3.22 × 10−9 for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10−8 for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10−4, 0.039, 4.86 × 10−5, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
► CSF tau and ptau levels provide more statistical power than case-control studies ► CSF tau levels as endophenotype for AD identified four loci implicated on AD
Cruchaga et al. use cerebrospinal fluid (CSF) tau levels as a quantitative trait for genetic studies of Alzheimer disease (AD). A genome-wide association study in over 1,200 individuals identifies genes that influence CSF tau levels and risk for AD.
Late-onset Alzheimer's disease (LOAD) is significantly more frequent in Hispanics than in non-Hispanic Whites. Ancestry may explain these differences across ethnic groups. To this end, we studied a ...large cohort of Caribbean Hispanics (CH, N = 8813) and tested the association between Local Ancestry (LA) and LOAD ("admixture mapping") to identify LOAD-associated ancestral blocks, separately for ancestral components (European EUR, African AFR, Native AmericanNA) and jointly (AFR + NA). Ancestral blocks significant after permutation were fine-mapped employing multi-ethnic whole-exome sequencing (WES) to identify rare variants associated with LOAD (SKAT-O) and replicated in the UK Biobank WES dataset. Candidate genes were validated studying (A) protein expression in human LOAD and control brains; (B) two animal AD models, Drosophila and Zebrafish. In the joint AFR + NA model, we identified four significant ancestral blocks located on chromosomes 1 (p value = 8.94E-05), 6 (p value = 8.63E-05), 21 (p value = 4.64E-05) and 22 (p value = 1.77E-05). Fine-mapping prioritized the GCAT gene on chromosome 22 (SKAT-O p value = 3.45E-05) and replicated in the UK Biobank (SKAT-O p value = 0.05). In LOAD brains, a decrease of 28% in GCAT protein expression was observed (p value = 0.038), and GCAT knockdown in Amyloid-β
Drosophila exacerbated rough eye phenotype (68% increase, p value = 4.84E-09). In zebrafish, gcat expression increased after acute amyloidosis (34%, p value = 0.0049), and decreased upon anti-inflammatory Interleukin-4 (39%, p value = 2.3E-05). Admixture mapping uncovered genomic regions harboring new LOAD-associated loci that might explain the observed different frequency of LOAD across ethnic groups. Our results suggest that the inflammation-related activity of GCAT is a response to amyloid toxicity, and reduced GCAT expression exacerbates AD pathology.
Purpose
To compare drusen size metrics (apical height and basal width) on optical coherence tomography (OCT) B-scans with their size assessed on color photos in eyes with age-related macular ...degeneration (AMD) and normal aging.
Methods
A total of 508 drusen were evaluated in this analysis. Flash color fundus photos (CFP), infrared reflectance (IR) images, and OCT B-scans obtained at the same visit were evaluated. Individual drusen were identified on CFPs and the diameters of the drusen were measured in planimetric grading software. CFPs were manually registered to the IR image with their corresponding OCT volume. After confirming correspondence between the CFP and OCT, the apical height and basal width of the same drusen were measured on OCT B-scans.
Results
Drusen were divided into small, medium, large, and very large categories based on their diameter on the CFP images (< 63, 63 to 124, 125 to 249, and
≥
250 μm, respectively). The OCT apical height of small drusen on CFP ranged from 20 to 31 μm, while medium drusen ranged from 31 to 46 μm, large drusen ranged from 45 μm to 111 µm, and very large drusen ranged from 55 μm to 208 μm. The OCT basal width measured < 99 μm in small drusen, from 99 to 143 μm in medium drusen, from 141 to 407 µm in large drusen, and > 209 µm in very large drusen.
Conclusion
Drusen of different size categories on color photographs may also be separated according to their apical height and basal width on OCT. The apical height and basal width ranges defined in this analysis may be of value in the design of an OCT-based grading scale for AMD.
Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of ...the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDF
