Rare coding variants and X-linked loci associated with age at menarche.
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ABSTRACT:
SUBMITTER: Lunetta KL
PROVIDER: S-EPMC4538850 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction: Genome-wide association studies (GWAS) have identified multiple loci associated with Parkinson's disease (PD) risk. The presence of rare variants within these loci that may account for the increased susceptibility requires further investigation. Methods: Using exome sequencing, we performed a comprehensive rare variant screen of genes located within 56 novel PD loci. We first analyzed exomes from 109 subjects in the discovery cohort (85 diagnosed with PD and 24 healthy controls) and filtered for rare coding variants with minor allele frequency <0.01 and combined annotation-dependent depletion > 15. Further investigation of exome data from a replication cohort of 2,859 European patients with PD (International Parkinson's Disease Genomics Consortium) and 24,146 non-Finnish European controls from gnomAD were used for association testing of specific rare variants found in the discovery cohort. Results: Our genetic screening identified 54 potential disease-relevant variants in 71 genes in 109 subjects. Six out of 54 variants were found in two or more patients and were not observed in healthy controls: DNAH1 p.A3639T, STAB1 p.S1089G, ANK2 p.V3634D, ANK2 p.R3906W, SH3GL2 p.G276V, and NOD2 p.G908R. Replication in the International Parkinson's Disease Genomics Consortium (IPDGC) confirmed the association with PD risk for three out of the six identified variants (STAB1 p.S1089G, SH3GL2 p.G276V, and NOD2 p.G908R) (p < 10-3). Conclusion: Our study suggests that some of the associations identified in PD risk loci can be ascribed to rare variants with likely functional effects that modify PD risk.
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Project description:Age at menarche and age at natural menopause are associated with causes of substantial morbidity and mortality such as breast cancer and cardiovascular disease. We conducted a joint analysis of two genome-wide association studies of these two traits in a total of 17,438 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 15,151). For age at menarche, we identified ten associated SNPs (P = 1 × 10(-7)-3 × 10(-13)) clustered at 6q21 (in or near the gene LIN28B) and 9q31.2 (in an intergenic region). For age at natural menopause, we identified 13 associated SNPs (P = 1 × 10(-7)-1 × 10(-21)) clustered at 20p12.3 (in the gene MCM8), 19q13.42 (in or near the gene BRSK1), 5q35.2 (in or near genes UIMC1 and HK3) and 6p24.2 (in the gene SYCP2L). These newly identified loci might expand understanding of the biological pathways regulating these two traits.
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Project description:Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks.
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Project description:Genome-wide association studies (GWAS) have identified 52 independent variants at 34 genetic loci that are associated with age-related macular degeneration (AMD), the most common cause of incurable vision loss in the elderly worldwide. However, causal genes at the majority of these loci remain unknown. In this study, we performed whole exome sequencing of 264 individuals from 63 multiplex families with AMD and analyzed the data for rare protein-altering variants in candidate target genes at AMD-associated loci. Rare coding variants were identified in the CFH, PUS7, RXFP2, PHF12 and TACC2 genes in three or more families. In addition, we detected rare coding variants in the C9, SPEF2 and BCAR1 genes, which were previously suggested as likely causative genes at respective AMD susceptibility loci. Identification of rare variants in the CFH and C9 genes in our study validated previous reports of rare variants in complement pathway genes in AMD. We then extended our exome-wide analysis and identified rare protein-altering variants in 13 genes outside the AMD-GWAS loci in three or more families. Two of these genes, SCN10A and KIR2DL4, are of interest because variants in these genes also showed association with AMD in case-control cohorts, albeit not at the level of genome-wide significance. Our study presents the first large-scale, exome-wide analysis of rare variants in AMD. Further independent replications and molecular investigation of candidate target genes, reported here, would assist in gaining novel insights into mechanisms underlying AMD pathogenesis.
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Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the world. While dozens of independent genomic variants are associated with AMD, about one-third of AMD heritability is still unexplained. To identify novel variants and loci for AMD, we analyzed Illumina HumanExome chip data from 87 Amish individuals with early or late AMD, 79 unaffected Amish individuals, and 15 related Amish individuals with unknown AMD affection status. We retained 37,428 polymorphic autosomal variants across 175 samples for association and linkage analyses. After correcting for multiple testing (n?=?37,428), we identified four variants significantly associated with AMD: rs200437673 (LCN9, p?=?1.50?×?10-11), rs151214675 (RTEL1, p?=?3.18?×?10-8), rs140250387 (DLGAP1, p?=?4.49?×?10-7), and rs115333865 (CGRRF1, p?=?1.05?×?10-6). These variants have not been previously associated with AMD and are not in linkage disequilibrium with the 52 known AMD-associated variants reported by the International AMD Genomics Consortium based on physical distance. Genome-wide significant linkage peaks were observed on chromosomes 8q21.11-q21.13 (maximum recessive HLOD?=?4.03) and 18q21.2-21.32 (maximum dominant HLOD?=?3.87; maximum recessive HLOD?=?4.27). These loci do not overlap with loci previously linked to AMD. Through gene ontology enrichment analysis with ClueGO in Cytoscape, we determined that several genes in the 1-HLOD support interval of the chromosome 8 locus are involved in fatty acid binding and triglyceride catabolic processes, and the 1-HLOD support interval of the linkage region on chromosome 18 is enriched in genes that participate in serine-type endopeptidase inhibitor activity and the positive regulation of epithelial to mesenchymal transition. These results nominate novel variants and loci for AMD that require further investigation.
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Project description:Accumulation of amyloid β protein (Aβ) due to increased generation and/or impaired degradation plays an important role in Alzheimer's disease (AD) pathogenesis. In this report, we describe the identification of rare coding mutations in the endothelin-converting enzyme 2 (ECE2) gene in 1 late-onset AD family, and additional case-control cohort analysis indicates ECE2 variants associated with the risk of developing AD. The 2 mutations (R186C and F751S) located in the peptidase domain in the ECE2 protein were found to severely impair the enzymatic activity of ECE2 in Aβ degradation. We further evaluated the effect of the R186C mutation in mutant APP-knockin mice. Overexpression of wild-type ECE2 in the hippocampus reduced amyloid load and plaque formation, and improved learning and memory deficits in the AD model mice. However, the effect was abolished by the R186C mutation in ECE2. Taken together, the results demonstrated that ECE2 peptidase mutations contribute to AD pathogenesis by impairing Aβ degradation, and overexpression of ECE2 alleviates AD phenotypes. This study indicates that ECE2 is a risk gene for AD development and pharmacological activation of ECE2 could be a promising strategy for AD treatment.
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Project description:Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17?mmol?l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.
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Project description:To date, common genetic variants in approximately 70 loci have been identified for breast cancer via genome-wide association studies (GWAS). It is unknown whether rare variants in these loci are also associated with breast cancer risk.We investigated rare missense/nonsense variants with minor allele frequency (MAF) ?5% located in flanking 500 kb of each of the index single-nucleotide polymorphism (SNP) in 67 GWAS loci. Included in the study were 3,472 cases and 3,595 controls from the Shanghai Breast Cancer Study. Both single marker and gene-based analyses were conducted to investigate the associations.Single marker analyses identified 38 missense variants being associated with breast cancer risk at P < 0.05 after adjusting for the index SNP. SNP rs146217902 in the EDEM1 gene and rs200340088 in the EFEMP2 gene were only observed in 8 cases (P = 0.004 for both). SNP rs200995432 in the EFEMP2 gene was associated with increased risk with an OR of 6.2 [95% confidence interval (CI), 1.4-27.6; P = 6.2 × 10(-3)]. SNP rs80358978 in the BRCA2 gene was associated with 16.5-fold elevated risk (95% CI, 2.2-124.5; P = 2.2 × 10(-4)). Gene-based analyses suggested eight genes associated with breast cancer risk at P < 0.05, including the EFEMP2 gene (P = 0.002) and the FBXO18 gene (P = 0.008).Our results identified associations of several rare coding variants neighboring common GWAS loci with breast cancer risk. Further investigation of these rare variants and genes would help to understand the biologic mechanisms underlying the associations.Independent studies with larger sample size are warranted to clarify the relationship between these rare variants and breast cancer risk.
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Project description:Purpose:A recent genome-wide association study by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) identified seven rare variants that are individually associated with age-related macular degeneration (AMD), the most common cause of vision loss in the elderly. In literature, several of these rare variants have been reported with different frequencies and odds ratios across populations of Europe and North America. Here, we aim to describe the representation of these seven AMD-associated rare variants in different geographic regions based on 24 AMD studies. Methods:We explored the occurrence of seven rare variants independently associated with AMD (CFH rs121913059 (p.Arg1210Cys), CFI rs141853578 (p.Gly119Arg), C3 rs147859257 (p.Lys155Gln), and C9 rs34882957 (p.Pro167Ser)) and three non-coding variants in or near the CFH gene (rs148553336, rs35292876, and rs191281603) in 24 AMD case-control studies. We studied the difference in distribution, interaction, and effect size for each of the rare variants based on the minor allele frequency within the different geographic regions. Results:We demonstrate that two rare AMD-associated variants in the CFH gene (rs121913059 [p.Arg1210Cys] and rs35292876) deviate in frequency among different geographic regions (p=0.004 and p=0.001, respectively). The risk estimates of each of the seven rare variants were comparable across the geographic regions. Conclusions:The results emphasize the importance of identifying population-specific rare variants, for example, by performing sequencing studies in case-control studies of various populations, because their identification may have implications for diagnostic screening and personalized treatment.
| S-EPMC5788811 | biostudies-literature
Project description:Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)-which encodes a circulating pro-angiogenic factor mainly secreted from the liver-shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA.
| S-EPMC5778084 | biostudies-literature