Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression.

Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS). However, the impact of rare coding variants on depression remains poorly understood. Here, we present whole-exome sequencing analyses of depression with seven different definitions based on survey, questionnaire, and electronic health records in 320,356 UK Biobank participants.

The impact of rare protein coding genetic variation on adult cognitive function.

Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects.

The burden of rare protein-truncating genetic variants on human lifespan.

Genetic predisposition has been shown to contribute substantially to the age at which we die. Genome-wide association studies (GWASs) have linked more than 20 loci to phenotypes related to human lifespan. However, little is known about how lifespan is impacted by gene loss of function.

Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes.

Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer's disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6, TSPAN14, NCK2 and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with >50% probability each of being causally involved in AD risk and others strongly suggested by functional annotation.

Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome.

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases.

Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization.

Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis.

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state-of-the-art methodologies.

Case-control association mapping by proxy using family history of disease.

Collecting cases for case-control genetic association studies can be time-consuming and expensive. In some situations (such as studies of late-onset or rapidly lethal diseases), it may be more practical to identify family members of cases. In randomly ascertained cohorts, replacing cases with their first-degree relatives enables studies of diseases that are absent (or nearly absent) in the cohort.

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A.

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.

Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time.

Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration.

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls.

Host genetic variants and gene expression patterns associated with Epstein-Barr virus copy number in lymphoblastoid cell lines.

Lymphoblastoid cell lines (LCLs) are commonly used in molecular genetics, supplying DNA for the HapMap and 1000 Genomes Projects, used to test chemotherapeutic agents, and informing the basis of a number of population genetics studies of gene expression. The process of transforming human B cells into LCLs requires the presence of Epstein-Barr virus (EBV), a double-stranded DNA virus which through B-cell immortalisation maintains an episomal virus genome in every cell of an LCL at variable copy numbers. Previous studies have reported that EBV alters host-gene expression and EBV copy number may be under host genetic control.

Whipworm genome and dual-species transcriptome analyses provide molecular insights into an intimate host-parasite interaction.

Whipworms are common soil-transmitted helminths that cause debilitating chronic infections in man. These nematodes are only distantly related to Caenorhabditis elegans and have evolved to occupy an unusual niche, tunneling through epithelial cells of the large intestine. We report here the whole-genome sequences of the human-infective Trichuris trichiura and the mouse laboratory model Trichuris muris.

Genetic studies of Crohn's disease: past, present and future.

The exact aetiology of Crohn's disease is unknown, though it is clear from early epidemiological studies that a combination of genetic and environmental risk factors contributes to an individual's disease susceptibility. Here, we review the history of gene-mapping studies of Crohn's disease, from the linkage-based studies that first implicated the NOD2 locus, through to modern-day genome-wide association studies that have discovered over 140 loci associated with Crohn's disease and yielded novel insights into the biological pathways underlying pathogenesis. We describe on-going and future gene-mapping studies that utilise next generation sequencing technology to pinpoint causal variants and identify rare genetic variation underlying Crohn's disease risk.

Generation of primary human intestinal T cell transcriptomes reveals differential expression at genetic risk loci for immune-mediated disease.

Objective: Genome-wide association studies (GWAS) have identified genetic variants within multiple risk loci as predisposing to intestinal inflammatory diseases, including Crohn's disease, ulcerative colitis and coeliac disease. Most risk variants affect regulation of transcription, but a critical challenge is to identify which genes and which cell types these variants affect. We aimed to characterise whole transcriptomes for each common T lymphocyte subset resident within the gut mucosa, and use these to infer biological insights and highlight candidate genes of interest within GWAS risk loci.

POT1 loss-of-function variants predispose to familial melanoma.

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors.