Polygenic overlap between C-reactive protein, plasma lipids, and Alzheimer disease

Background—Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. Methods and Results—Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05–1.11; P=2.86×10−8) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04–1.11; P=3.38×10−8). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. Conclusions—We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.acceptedVersio

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Publisher Copyright: © 2023, The Author(s).Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.Peer reviewe

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Identification of genetic loci shared between ADHD, intelligence and educational attainment

Background Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is consistently associated with lower levels of educational attainment. A recent large genome-wide association study identified common gene variants associated with ADHD, but most of the genetic architecture remains unknown. Methods We analyzed independent genome-wide association study summary statistics for ADHD (19,099 cases and 34,194 controls), educational attainment ( N = 842,499), and general intelligence ( N = 269,867) using a conditional/conjunctional false discovery rate (FDR) statistical framework that increases power of discovery by conditioning the FDR on overlapping associations. The genetic variants identified were characterized in terms of function, expression, and biological processes. Results We identified 58 linkage disequilibrium–independent ADHD-associated loci (conditional FDR < 0.01), of which 30 were shared between ADHD and educational attainment or general intelligence (conjunctional FDR < 0.01) and 46 were novel risk loci for ADHD. Conclusions These results expand on previous genetic and epidemiological studies and support the hypothesis of a shared genetic basis between these phenotypes. Although the clinical utility of the identified loci remains to be determined, they can be used as resources to guide future studies aiming to disentangle the complex etiologies of ADHD, educational attainment, and general intelligence

Sex-Based Differences in Incidence of Inflammatory Bowel Diseases-Pooled Analysis of Population-Based Studies From Western Countries.

To access publisher's full text version of this article click on the hyperlink belowAlthough the incidence of inflammatory bowel diseases (IBDs) varies with age, few studies have examined variations between the sexes. We therefore used population data from established cohorts to analyze sex differences in IBD incidence according to age at diagnosis. We identified population-based cohorts of patients with IBD for which incidence and age data were available (17 distinct cohorts from 16 regions of Europe, North America, Australia, and New Zealand). We collected data through December 2016 on 95,605 incident cases of Crohn's disease (CD) (42,831 male and 52,774 female) and 112,004 incident cases of ulcerative colitis (UC) (61,672 male and 50,332 female). We pooled incidence rate ratios of CD and UC for the combined cohort and compared differences according to sex using random effects meta-analysis. Female patients had a lower risk of CD during childhood, until the age range of 10-14 years (incidence rate ratio, 0.70; 95% CI, 0.53-0.93), but they had a higher risk of CD thereafter, which was statistically significant for the age groups of 25-29 years and older than 35 years. The incidence of UC did not differ significantly for female vs male patients (except for the age group of 5-9 years) until age 45 years; thereafter, men had a significantly higher incidence of ulcerative colitis than women. In a pooled analysis of population-based studies, we found age at IBD onset to vary with sex. Further studies are needed to investigate mechanisms of sex differences in IBD incidence

GSV analysis of candidate obesity loci.

<p>SNP genotyping data from 3 separate cohorts were analysed using the cnvHap algorithm, and GSVs were identified that corresponded to the GSVs under investigation. For GSVs identified in at least one individual, association with obesity status (excluding overweight individuals from the analysis) was tested according to Fisher’s exact test. For GSVs identified in at least 3 members of the NFBC1966 cohort, association with log₁₀BMI as a quantitative trait was tested by 2-way ANOVA with gender as the second covariate. Italics denote a direction of effect opposite to that in the original report.</p>a<p>refers to the Illumina Human CNV370 array.</p>b<p>re-calculated after excluding individuals with deletions of the neighbouring 16p11.2 obesity-associated region (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058048#pone.0058048.s006" target="_blank">Text S1</a>).</p

Procedure for identification of GSVs.

<p>Following data export and QC, GSV calling was carried out using the cnvHap algorithm. Illustrative data for 3 GSV loci (shaded) show all positive GSV calls (black) together with examples of calls not meeting the necessary criteria (grey); probes at which copy number changes were identified are also indicated (circles).</p