The pathobiology of idiopathic pulmonary fibrosis remains largely unknown. In this study, a variety of genetic techniques were used to implicate variants in the mucin-forming gene
MUC5B
as pivotal in ...a substantial proportion of patients with the disorder.
The evidence that there is a genetic basis for idiopathic interstitial pneumonia is substantial, with familial aggregation confirmed through studies in twins, siblings raised apart, and multigenerational families.
1
Interstitial lung disease has been associated with several pleiotropic genetic disorders.
2
The development of pulmonary fibrosis has been associated with private mutations in surfactant protein C,
3
surfactant protein A2,
4
and genes that maintain telomere length.
5
However, collectively these mutations account for a small proportion of the population risk of idiopathic interstitial pneumonia.
In this article, we used a genomewide linkage scan to identify a risk locus for idiopathic interstitial pneumonia on the . . .
Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by ...considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry‐adjusted and ‐unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real‐world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the genotype parameters of adjusted and unadjusted models all provide tests for LD between the marker and trait locus, but in different contexts. The local ancestry adjusted model tests for LD in the ancestral populations, while tests using the unadjusted and the global ancestry adjusted models depend on LD in the admixed population(s), which may be enriched due to different ancestral allele frequencies. Practically, this implies that global‐ancestry adjustment should be used for screening, but local‐ancestry adjustment may better inform fine mapping and provide better effect estimates at trait loci.
Introduction
Our understanding of the genetic predisposition for age‐at‐onset (AAO) of Alzheimer's disease (AD) is limited. Here, we sought to identify genes modifying AAO and examined whether any ...have sex‐specific effects.
Methods
Genome‐wide association analysis were performed on imputed genetic data of 9219 AD cases and 10,345 controls from 20 cohorts of the Alzheimer's Disease Genetics Consortium. AAO was modeled from cases directly and as a survival outcome.
Results
We identified 11 genome‐wide significant loci (P < 5 × 10−8), including six known AD‐risk genes and five novel loci, UMAD1, LUZP2, ARFGEF2, DSCAM, and 4q25, affecting AAO of AD. Additionally, 39 suggestive loci showed strong association. Twelve loci showed sex‐specific effects on AAO including CD300LG and MLX/TUBG2 for females and MIR4445 for males.
Discussion
Genes that influence AAO of AD are excellent therapeutic targets for delaying onset of AD. Several loci identified include genes with promising functional implications for AD.
Several lines of evidence suggest that genetic factors and environmental exposures play a role in the development of pulmonary fibrosis.
We evaluated families with 2 or more cases of idiopathic ...interstitial pneumonia among first-degree family members (familial interstitial pneumonia, or FIP), and identified 111 families with FIP having 309 affected and 360 unaffected individuals.
The presence of probable or definite FIP was based on medical record review in 28 cases (9.1%); clinical history, diffusing capacity of carbon monoxide (DL(CO)), and chest X-ray in 16 cases (5.2%); clinical history, DL(CO), and high-resolution computed tomography chest scan in 191 cases (61.8%); clinical history and surgical lung biopsy in 56 cases (18.1%); and clinical history and autopsy in 18 cases (5.8%).
Older age (68.3 vs. 53.1; p < 0.0001), male sex (55.7 vs. 37.2%; p < 0.0001), and having ever smoked cigarettes (67.3 vs. 34.1%; p < 0.0001) were associated with the development of FIP. After controlling for age and sex, having ever smoked cigarettes remained strongly associated with the development of FIP (odds ratio(adj), 3.6; 95% confidence interval, 1.3-9.8). Evidence of aggregation of disease was highly significant (p < 0.001) among sibling pairs, and 20 pedigrees demonstrated vertical transmission, consistent with autosomal dominant inheritance. Forty-five percent of pedigrees demonstrated phenotypic heterogeneity, with some pedigrees demonstrating several subtypes of idiopathic interstitial pneumonia occurring within the same families.
These findings suggest that FIP may be caused by an interaction between a specific environmental exposure and a gene (or genes) that predisposes to the development of several subtypes of idiopathic interstitial pneumonia.
To conduct a genome-wide association study (GWAS) of individuals with neuropathic ocular pain (NOP) symptoms to identify genomic variants that may predispose to NOP development.
Prospective study of ...individuals with NOP.
Three hundred twenty-nine patients recruited from the Miami Veterans Affairs eye clinic.
The Neuropathic Pain Symptom Inventory modified for the eye (NPSI-Eye) was completed to calculate a NPSI-Eye-Sub-Score (summed ratings of burning and wind sensitivity) as an indicator of NOP severity. A GWAS was performed for the NPSI-Eye-Sub-Score with a significance threshold of P < 5 × 10−8. A gene-based analysis was performed using the multimarker analysis of genomic annotation software (in the functional mapping and annotation of GWAS online platform). The 13 865 778 single nucleotide polymorphisms (SNPs) from our GWAS analysis were mapped to 10 834 protein coding genes, and significant genes were run through gene set enrichment analysis.
Identification of SNPs and protein products that may be associated with the development of NOP.
One hundred seventy-one SNPs reached a threshold of P < 10−5, of which 10 SNPs reached the suggestive level of significance of P < 5 × 10−7 and 1 SNP met our genome-wide significance threshold of P < 5 × 10−8. This lead SNP, rs140293404 (P = 1.23 × 10−8), is an intronic variant found within gene ENSG00000287251 coding for transcript ENST00000662732.1. Rs140293404 is in linkage disequilibrium with exon variant rs7926353 (r2 > 0.8) within ENSG00000279046 coding for transcript ENST00000624288.1. The most significant genes from gene-based tests were matrix metalloproteinase-19 (MMP19) (P = 1.12 × 10−5), zinc finger RNA-binding motif and serine/arginine rich-1 (ZRSR1) (P = 1.48 × 10−4), CTC-487M23.8 (P = 1.79 × 10−4), receptor expression-enhancing protein-5 (REEP5) (P = 2.36 × 10−4), and signal recognition particle-19 (SRP19) (P = 2.56 × 10−4). From gene set enrichment analysis, the sensory perception (false discovery rate = 6.57 × 10−3) and olfactory signaling (false discovery rate = 1.63 × 10−2) pathways were enriched with the most significant genes.
Our GWAS revealed genes with protein products that may impact sensory perception, lending biological plausibility to a role for SNPs identified by our GWAS in the development of NOP. A better understanding of the biological relevance of these genes and pathways in the pathophysiology associated with NOP may facilitate future novel mechanism-based treatments.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Adjuvant radiotherapy (RT) can increase the risk of developing pain; however, the molecular mechanisms of RT-related pain remain unclear. The current study aimed to identify susceptibility loci and ...enriched pathways for clinically relevant acute post-RT pain, defined as having moderate to severe pain (pain score ≥ 4) at the completion of RT.
We conducted a genome-wide association study (GWAS) with 1,344,832 single-nucleotide polymorphisms (SNPs), a gene-based analysis using PLINK set-based tests of 19,621 genes, and a functional enrichment analysis of a gene list of 875 genes with p < 0.05 using NIH DAVID functional annotation module with KEGG pathways and GO terms (n = 380) among 1112 breast cancer patients.
About 29% of patients reported acute post-RT pain. None of SNPs nor genes reached genome-wide significant level. Four SNPs showed suggestive associations with post-RT pain; rs16970540 in RFFL or near the LIG3 gene (p = 1.7 × 10
), rs4584690, and rs7335912 in ABCC4/MPR4 gene (p = 5.5 × 10
and p = 7.8 × 10
, respectively), and rs73633565 in EGFL6 gene (p = 8.1 × 10
). Gene-based analysis suggested the potential involvement of neurotransmitters, olfactory receptors, and cytochrome P450 in post-RT pain, whereas functional analysis showed glucuronidation (FDR-adjusted p value = 9.46 × 10
) and olfactory receptor activities (FDR-adjusted p value = 0.032) as the most significantly enriched biological features.
This is the first GWAS suggesting that post-RT pain is a complex polygenic trait influenced by many biological processes and functions such as glucuronidation and olfactory receptor activities. If validated in larger populations, the results can provide biological targets for pain management to improve cancer patients' quality of life. Additionally, these genes can be further tested as predictive biomarkers for personalized pain management.
Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and ...behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered.
To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized.
We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P = 8.55 × 10-5).
By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases.
Non-syndromic cleft lip with or without cleft palate (NSCLP) is the most common craniofacial birth defect. The etiology of NSCLP is complex with multiple genes and environmental factors playing ...causal roles. Although studies have identified numerous genetic markers associated with NSCLP, the role of epigenetic variation remains relatively unexplored. Because of their identical DNA sequences, monozygotic (MZ) twins discordant for NSCLP are an ideal model for examining the potential contribution of DNA methylation to non-syndromic orofacial clefting. In this study, we compared the patterns of whole genome DNA methylation in six MZ twin pairs discordant for NSCLP. Differentially methylated positions (DMPs) and regions (DMRs) were identified in NSCLP candidate genes, including differential methylation in
and
in two independent MZ twin pairs. In addition to DNA methylation differences in NSCLP candidate genes, we found common differential methylation in genes belonging to the Hippo signaling pathway, implicating this mechanosensory pathway in the etiology of NSCLP. The results of this novel approach using MZ twins discordant for NSCLP suggests that differential methylation is one mechanism contributing to NSCLP, meriting future studies on the role of DNA methylation in familial and sporadic NSCLP.
Background
Alzheimer disease (AD) is a degenerative brain disease, being the most common cause of progressive dementia and listed as the sixth leading cause of mortality in the USA. It is often ...described as either early onset (EOAD, age at onset, AAO <= 65) or late onset (LOAD, AAO>65). Non‐Mendelian EOAD (not monogenic; nmEOAD) has irregular inheritance patterns and fluctuating AAO, characteristics also present in LOAD cases. There is still a lack of evidence in the literature depicting the similarities (if any) between nmEOAD and LOAD forms, being unclear how much genetic etiology is shared by the two forms of AD. To shed light to this question, a genome‐wide association study (GWAS) and heritability analyses of nmEOAD and LOAD were performed.
Method
Genetic data on 21,622 individuals from the Alzheimer Disease Genetics Consortium (ADGC) were used: (1,476 nmEOAD, 9,695 LOAD and 10,451 control). Single‐variant association analyses were performed using logistic regression under two models: (1) ancestry plus SNP, and (2) ancestry, sex, APOE dosage, and SNP. nmEOAD and LOAD were considered separately. LD score regression was used to estimate the SNP heritability (h2) and genetic correlation (rg), considering two additional models: (3) ancestry, sex, and SNP and (4) ancestry, APOE dosage and SNP.
Result
Several known candidate genes confirmed for LOAD along with novel regions associated with immune and cell‐signaling pathways in nmEOAD models. Gene based tests showed significant association for APOE gene (Chr19): nmEOAD (p=3.89x10‐16 and p=4.29x10‐12) and LOAD (p=1.07x10‐65 and p=1.12x10‐14), models (1) and (2) respectively. Heritability analyses showed higher h2 values for EOAD (h2=0.24, 0.23, 0.25 and 0.24) than LOAD (h2=0.18, 0.14, 0.18, and 0.14) for models (1) to (4) respectively. Genetic correlation showed moderate genetic overlap between EOAD and LOAD only for models: (2) rg=0.35 (p=0.0283) and (4) rg=0.34 (p=0.0261).
Conclusion
GWAS and heritability analysis suggest that the genetic etiology of EOAD has a noncomplete genetic overlap with LOAD, with a moderate overlap when APOE dosage is modeled and a minimal overlap otherwise (APOE effect). The results also suggest a stronger polygenic effect in EOAD than LOAD, confirming the need for additional genomics efforts in nmEOAD.
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