Brian L. Yaspan

Extract Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease thought to result from an aberrant response to lung injury, culminating in an exaggerated healing response with excessive deposition of extracellular matrix in the interstitium [1].

Age-related macular degeneration (AMD) is a multifactorial retinal disease with a large genetic risk contribution. Reticular pseudodrusen (RPD) is a sub-phenotype of AMD with a high risk of progression to late vision threatening AMD. In a genome-wide association study of 2165 AMD+/RPD+ and 4181 AMD+/RPD- compared to 7639 control participants, both chromosomes 1 (CFH) and 10 (ARMS2/HTRA1) major AMD risk loci are reidentified. However association is only detected for the chromosome 10 locus when comparing AMD+/RPD+ to AMD+/RPD- cases. The chromosome 1 locus is notably absent. The chromosome 10 RPD risk region contains a long non-coding RNA HTRA1-AS1 (ENSG00000285955/BX842242.1) which colocalizes with genetic markers of retinal thickness. HTRA1-AS1 has a strong retinal eQTL signal, pinpointing the parafoveal photoreceptor outer segment layer. Whole genome sequencing of phenotypically extreme RPD cases identifies even stronger enrichment for the chromosome 10 risk genotype.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic association signals have been reported for IPF susceptibility, but these have been discovered when combining males and females.Objectives: To assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF and to test for sex-specific associations with IPF susceptibility.Methods: We performed a genome-wide single nucleotide polymorphism (SNP)-by-sex interaction study meta-analysis of IPF risk in six independent case-control studies. comprising 4561 cases (1280 females, 2281 males) and 23 500 controls (8360 females, 14 528 males) of European genetic ancestry. We used polygenic risk scores (PRS) comprising common (minor allele frequency>1%) autosomal variants to assess differences in genetic risk prediction between males and females.Results: The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific association results. Three new independent genetic association signals were identified (p−6).Conclusions: The predictive accuracy of common autosomal SNP-based PRSs did not vary significantly between males and females. We prioritised three genetic variants whose effect on IPF risk may be modified by sex. These findings would not account for the differences in prevalence between males and females. Future studies should ensure adequate representation of both sexes.

Introduction: Acute respiratory distress syndrome (ARDS) is a severe inflammatory process of the lung, often due to sepsis, and poses significant mortality burden in intensive care units. Here we conducted the largest genome-wide association study (GWAS) of sepsis-associated ARDS to identify novel genetic risk loci that can help guide the development of new therapeutic options. Methods: We performed a case-control GWAS in 716 patients with sepsis-associated ARDS and 4,399 at-risk sepsis controls from three independent studies. Results were meta-analysed across the three studies, with significance set at p -8 . Suggestive associations were declared for variants exhibiting consistent effects, likely to replicate and nominal significance ( p in-silico functional assessments, and gene-based rare variant collapsing analysis using whole exome sequencing (WES) data. Two independent studies with 430 ARDS cases and 1,398 controls served as replication samples. Results: We identified a variant showing genome-wide significant association with sepsis-associated ARDS risk intergenic to ANKRD31 and HMGCR , previously linked to cholesterol metabolism. Suggestive associations were found for eight other variants. The rare exonic variant analysis showed associations between HMGCR and POC5 and sepsis-associated ARDS at nominal level ( p ANKRD31 and HMGCR was associated with sepsis-associated ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed.

To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a major histocompatibility complex class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies.

Age-related macular degeneration (AMD), a complex neurodegenerative disease, is a leading cause of visual impairment worldwide with a strong genetic component. Genetic studies have identified several loci, but few causal genes with functional characterization. Here we highlight multiple lines of evidence which show a causal role in AMD for SLC16A8, which encodes MCT3, a retinal pigment epithelium (RPE) specific lactate transporter. First, in an unbiased, genome-wide analysis of rare coding variants we show multiple SLC16A8 rare variants are associated with AMD risk, corroborating previous borderline significant reports from AMD rare variant studies. Second, we report a novel SLC16A8 mutation in a three-generation family with early onset macular degeneration. Finally, mis-expression in multiple model organisms shows functional and anatomic retinal consequences. This study highlights the important role for SLC16A8 and lactate regulation towards outer retina/RPE health and highlights a potential new therapeutic opportunity for the treatment of AMD.

Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory ‘states’ that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states. This process identifies regulators of five distinct states associated with key features of macrophage function. Among these regulators, loss of the N⁶-methyladenosine (m6A) writer components abolishes m6A modification of TNF transcripts, thereby enhancing mRNA stability and TNF production associated with multiple inflammatory pathologies. Thus, phenotypic characterization of primary murine and human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic variants have been identified to be associated with IPF susceptibility, but these have been discovered when combining males and females. Our aim was to test for the presence of sex-specific associations with IPF susceptibility and assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF. Methods: We performed genome-wide single nucleotide polymorphism (SNP)-by-sex interaction studies of IPF risk in six independent IPF case-control studies and combined them using inverse-variance weighted fixed effect meta-analysis. In total, 4,561 cases (1,280 females and 2,281 males) and 23,500 controls (8,360 females and 14,528 males) of European genetic ancestry were analysed. We used polygenic risk scores (PRS) to assess differences in genetic risk prediction between males and females. Findings: Three independent genetic association signals were identified. All showed a consistent direction of effect across all individual IPF studies and an opposite direction of effect in IPF susceptibility between females and males. None had been previously identified in IPF susceptibility genome-wide association studies (GWAS). The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific GWAS results. Interpretation: We prioritised three genetic variants whose effect on IPF risk may be modified by sex, however these require further study. We found no evidence that the predictive accuracy of common SNP-based PRSs varies significantly between males and females. Research in context: Evidence before this study: The prevalence of IPF is higher in males than females. IPF risk has a genetic component, but analyses have only been performed in studies where males and females have been combined. One previous study reported sex-specific differences in association for the MUC5B promoter variant, rs35705950, however the finding was not replicated in an independent study. No genome-wide association studies assessing for different genetic risk factors between males and females have been conducted for IPF. It is not known whether approaches to predict individuals at risk of IPF should take sex- specific genetic risk into consideration. Added value of this study: This was the largest study to test whether there are genetic variants whose effects on IPF susceptibility are different in males and females. The MUC5B promotor variant rs35705950 did not show a different magnitude of effect in males vs females. We identified three genetic variants with opposite directions of effect on IPF risk in males vs females. Our polygenic risk score analyses suggested that genetic prediction based on data from males and females separately did not perform better than when males and females were combined. Implications of all available evidence: Although we found some preliminary evidence of genetic variants with sex-specific effects on IPF risk, our analyses suggest that genome-wide genetic risk from common single nucleotide polymorphisms is similar in males and females. This is important when considering integration of polygenic risk scores into clinical prediction models for IPF. There may be other forms of genetic variation, such as complex structural variation or rare variants, not captured in this analysis, that may improve risk prediction for males and females separately.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of theHLA-DQB1gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk.Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case–control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p90% were considered significant. We sought to replicate the previously reportedHLA-DQB1association in the subset of studies independent of the original report.Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. TheHLA-DQB1association was not replicated in the independent IPF studies.Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.