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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 a genome-wide association study (GWAS) of ARDS to identify genetic risk loci that can help guide the development of new therapeutic options. We performed a case-control GWAS in 716 cases with ARDS, mainly associated with severe infections, and 4399 at-risk controls from three independent studies. Results were meta-analysed across the three studies, with significance set at p < 5 × 10 We identified a variant near HMGCR that showed genome-wide significant association with ARDS and had been previously linked to cholesterol metabolism. This locus was associated with ANKDD1B expression in artery. The rare exonic variant analysis showed associations between HMGCR and ARDS at nominal level (p < 0.05). While no nominal significance was achieved in the two additional validation cohorts, this variant exhibited a consistent direction of effects across all 5 studies. A common variant near HMGCR was associated with ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed. Wellcome Trust, National Institute for Health Research Leicester Biomedical Research Centre, National Heart, Lung, and Blood Institute, ATS Research Program, Gobierno de Canarias, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Instituto Tecnológico y de Energías Renovables, Cabildo Insular de Tenerife, Instituto de Salud Carlos III, Agencia Estatal de Investigación, German Ministry of Education and Research, Thuringian Ministry of Education, Science and Culture, the Thuringian Foundation for Technology, Innovation, and Research, German Sepsis Society. Show less

The genetic component of early-onset Alzheimer disease (EOAD), accounting for ~10% of all Alzheimer's disease (AD) cases, is largely unexplained. Recent studies suggest that EOAD may be enriched for variants acting in the lipid pathway. The current study examines the shared genetic heritability between EOAD and the lipid pathway using genome-wide multi-trait genetic covariance analyses. Summary statistics were obtained from the GWAS meta-analyses of EOAD by the Alzheimer's Disease Genetics Consortium (n=19,668) and five blood lipid traits by the Global Lipids Genetics Consortium (n=1,320,016). The significant results were compared between the EOAD and lipids GWAS and genetic covariance analyses were performed via SUPERGNOVA. Genes in linkage disequilibrium (LD) with top EOAD hits in identified regions of covariance with lipid traits were scored and ranked for causality by combining evidence from gene-based analysis, AD-risk scores incorporating transcriptomic and proteomic evidence, eQTL data, eQTL colocalization analyses, DNA methylation data, and single-cell RNA sequencing analyses. Direct comparison of GWAS results showed 5 loci overlapping between EOAD and at least one lipid trait harboring APOE, TREM2, MS4A4E, LILRA5, and LRRC25. Local genetic covariance analyses identified 3 regions of covariance between EOAD and at least one lipid trait. Gene prioritization nominated 3 likely causative genes at these loci: ANKDD1B, CUZD1, and MS4A64.The current study identified genetic covariance between EOAD and lipids, providing further evidence of shared genetic architecture and mechanistic pathways between the two traits. Show less

Migraine is a common neurological disorder that affects more than one billion people worldwide. Recent genome-wide association studies have identified 123 genetic loci associated with migraine risk. However, the biological mechanisms underlying migraine and its relationships with other complex diseases remain unclear. We performed a phenome-wide association study (PheWAS) using UK Biobank data to investigate associations between migraine and 416 phenotypes. Mendelian randomization was employed using the IVW method. For loci associated with multiple diseases, pleiotropy was tested using MR-Egger. Single-cell RNA sequencing data was analyzed to profile the expression of 73 migraine susceptibility genes across brain cell types. qPCR was used to validate the expression of selected genes in microglia. PheWAS identified 15 disorders significantly associated with migraine, with one association detecting potential pleiotropy. Single-cell analysis revealed elevated expression of seven susceptibility genes (including ZEB2, RUNX1, SLC24A3, ANKDD1B, etc.) in brain glial cells. And qPCR confirmed the upregulation of these genes in LPS-treated microglia. This multimodal analysis provides novel insights into the link between migraine and other diseases. The single-cell profiling suggests the involvement of specific brain cells and molecular pathways. Validation of gene expression in microglia supports their potential role in migraine pathology. Overall, this study uncovers pleiotropic relationships and the biological underpinnings of migraine susceptibility. Show less

Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background. The aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort. In this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom's MALDI-TOF iPLEX platform. In univariate analysis, The study indicates that there is an association between Show less

Hypertension, clinically defined by elevated blood pressure (BP), is an important cause of mortality and morbidity worldwide. Many risk factors for hypertension are known, including a positive family history, which suggests that genetics contribute to interindividual BP variation. Genome-wide association studies (GWAS) have identified > 1000 loci associated with BP, yet the identity of the genes responsible for these associations remains largely unknown. To pinpoint genes that causally affect variation of BP in humans, we analyzed predicted loss-of-function (pLoF) variants in the UK Biobank whole-exome sequencing dataset (n = 454,709 participants, 6% non-European ancestry). We analyzed genetic associations between systolic or diastolic BP (SBP/DBP) and single pLoF variants (additive and recessive genetic models) as well as with the burden of very rare pLoF variants (minor allele frequency [MAF] < 0.01%). Single pLoF variants in 10 genes were associated with BP (ANKDD1B, ENPEP, PNCK, BTN3A2, C1orf145 [OBSCN-AS1], CASP9, DBH, KIAA1161 [MYORG], OR4X1, and TMC3). We also found a burden of rare pLoF variants in 5 additional genes associated with BP (TTN, NOS3, FES, SMAD6, COL21A1). Except for PNCK, which is located on the X-chromosome, these genes map near variants previously associated with BP by GWAS, validating the study of pLoF variants to prioritize causal genes at GWAS loci. Our study highlights 15 genes that likely modulate BP in humans, including 5 genes that harbour pLoF variants associated with lower BP. Show less

Early studies have indicated that the risk of migraine is contributed by both genetic and environmental factors. We aimed to evaluate the association between the risk of migraine and genetic polymorphisms in the ANKDD1B gene in a large sample of Chinese Han populations. A total of 882 patients with MO and 1,784 age-matched controls were recruited. A list of 12 tag SNPs located within the ANKDD1B gene region was genotyped. Distributions of SNP genotypes and alleles between patients and controls were examined to investigate the associations between the risk of migraine and genetic polymorphisms. The GTEx database was used to examine the effects of the significant SNPs on gene expressions. A stop-gain SNP, rs34358, was discovered to be significantly related with the risk of migraine (χ Show less

This study aimed to identify new genes associated with CRC in patients with normal mismatch repair (MMR) protein expression. Whole-genome sequencing (WGS) was performed in seven early-age-onset Malay CRC patients. Potential germline genetic variants, including single-nucleotide variations and insertions and deletions (indels), were prioritized using functional and predictive algorithms. An average of 3.2 million single-nucleotide variations (SNVs) and over 800 indels were identified. Three potential candidate variants in three genes- This study provides a new spectrum of insights into the potential genes, variants and pathways associated with CRC in Malay patients. Show less

To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions. We evaluated phenotypic associations between migraine and 19 lipoprotein subfraction measures in the Women's Genome Health Study (n = 22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium for migraine (n There was a significant phenotypic association (odds ratio 1.27 [95% confidence interval 1.12-1.44]) and a significant genetic correlation at 0.18 ( The study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may help identify potential targets for future migraine therapeutics. This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions. Show less

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (N Show less

Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene-based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h Show less

Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. The genetics of AS is unclear. Analysis of rare AS pedigrees might facilitate our understanding of AS pathogenesis. We used genome-wide linkage analysis and whole-exome sequencing in combination with variant co-segregation verification and haplotype analysis to study an AS pedigree and a sporadic AS patient. We identified a missense variant in the ankyrin repeat and death domain containing 1B gene ANKDD1B from a Han Chinese pedigree with dominantly inherited AS. This variant (p.L87V) co-segregates with all male patients of the pedigree. In females, the penetrance of the symptoms is incomplete with one identified patient out of 5 carriers, consistent with the reduced frequency of AS in females of the general population. We further identified a distinct missense variant affecting a conserved amino acid (p.R102L) of ANKDD1B in a male from 30 sporadic early onset AS patients. Both variants are absent in 500 normal controls. We determined the haplotypes of four major known AS risk loci, including HLA-B*27, 2p15, ERAP1 and IL23R, and found that only HLA-B*27 is strongly associated with patients in our cohort. Together these results suggest that ANKDD1B variants might be associated with AS and genetic analyses of more AS patients are warranted to verify this association. Show less