A great read👇 Some social science genetics papers are among the most interesting and methodologically rigorous I've read. From biology to mating choices and inequalities, they deal with very fundamental concepts of what makes as humans.

Extremely proud to see this work led by @mihkeljesse.bsky.social now out on biorxiv!

I'm often asked how human genetic data can be used to validate drug targets. In our new ‪@natcardiovascres.nature.com‬ paper, we provide an end-to-end framework for genetically validating IL-6 inhibition for atherosclerotic cardiovascular disease outcomes 🧵

IL-6 inhibition lower risks of cardiovascular disease with no increase in infection, supporting pharmacological treatments of IL-6 rather than its receptor @natcardiovascres.nature.com @mariosgeorgakis.bsky.social www.nature.com/articles/s44... www.nature.com/articles/s44...

Amid the hype of using polygenic scores for embryo selection, some thoughts on their implementation potential in real-world settings (and problems) 👇

The modern cardiovascular drug development landscape has been largely shaped by human genetic studies. Emerging IL-6 therapeutics are a landmark example. In this paper with the Tourmaline Bio team, we review how genetics pinpointed IL-6 signaling as a causal driver of athero-inflammation👇

We recently published a preprint with the protocol & pilot data from 𝐀𝐭𝐡𝐞𝐫𝐎𝐌𝐈𝐂𝐒. AtherOMICS is a biobanking project built in our lab over the past 3 years aiming to provide access to multi-omics/multi-modal data from human atherosclerotic tissue❗ Some innovations of AtherOMICS👇

🚨ICYMI 🫀🧬 from @mariosgeorgakis.bsky.social & co 📄Single-cell transcriptome-wide Mendelian randomization and colocalization analyses uncover cell-specific mechanisms in atherosclerotic cardiovascular disease

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Yet, we lack circulating biomarkers for systemic atherosclerosis burden. Check out our new preprint describing the development of proteomic signatures of atherosclerosis👇

Facial characterisics are to a very large extent genetically determined🧬🤓 Now, it seems we could use genetic variation to predict 3D face structures with key implications for both forensic science and ethics👇

I read the latest GWAS on long COVID. Is it just me, or is it odd that the main analysis used population controls (broad definition) instead of individuals with SARS-CoV-2 infection without long COVID (strict definition)?

A new IL-6–targeting agent enters the inflammation space in cardiovascular disease❗️ Pacibekitug (Tourmaline Bio), an s.c. anti-IL6 mAb showed hsCRP reductions in patients with stage 3/4 CKD and hsCRP>2 mg/dl in phase 2. Big advantage the potential for quarterly dosing💉

Interesting paper on sex differences in the genetic regulation of the plasma proteome in Fenland (N=8348, SomaLogic) and UKB (N=48,017, Olink)👇

Great review of the evolving landscape of therapeutics targeting triglycerides & remnant cholesterol. Human genetics has been key to shaping this field with discoveries of loss-of-function variants in APOC3, ANGPTL3, ANGPTL4 having directly triggered clinical development 🧬-->💊

A great week for genetics, omics, and precision medicine — many exciting reads 🧬 1⃣ Circadian gene expression regulation by rhythmic genetic variants 🧵[1/8]

Profiling the proteome has turned out to be a challenging task. Available platforms offer increasingly broader coverage, but often yield different results for the same proteins. This preprint compares quantifications of mass spectrometry & Olink in the same samples👇

Most disease-associated GWAS signals fall in the non-coding genome🧬 Although assumed to influence expression, pinpointing the causal gene isn't easy. Two ways include: 1⃣eQTL mapping in relevant tissues/cells 2⃣in vitro CRISPRi screens This preprint compares the two👇

Exciting reads on genetics, omics, & precision medicine this week 🧬 1⃣ Tissue-specific atlas of protein co-abundance [1/6] 🧵

Two presentations from our lab this week🚨 👉Lanyue Zhang, awarded a Young Investigator Fellowship, on proteomic signatures of atherosclerosis at the EAS Congress in Glasgow 👉Anushree Ray, recipient of a Travel Award, on single-cell drivers of atherosclerosis at the CHARGE meeting in Maryland

Two meta-analyses in Eur Heart J, pool the available trial data on the use of colchicine for secondary prevention of cardiovascular events. Slight differences in inclusion criteria (e.g. long-term vs. any use), but both generally point to a benefit.

Genomic research largely overrepresents European ancestry individuals. This map shows the genomic ancestry of individuals recruited to All of Us across US states. While still predominantly European, it is possibly one of the most diverse biomedical datasets out there.

A very nice paper applying spatial single-cell transcriptomics (Stereo-seq) to human carotid plaques❗️ It identifies tertiary lymphoid organs within plaques and links them to symptomatic cerebrovascular disease (stroke/TIA) 🧠

Most GWAS and Mendelian randomization (MR) studies focus on trait exposures measured at a single time point🧬 A new approach introduces a framework for MR analyses that captures trait trajectories over time📈

Reads and resources that caught my eye on genetics, omics, and deep phenotyping this week 🧬 1⃣ A new multimorbidity framework for disease risk prediction [1/8]🧵

Additional data highlight the strong impact of elevated Lp(a) — which is highly genetically determined — on atherosclerotic cardiovascular disease. 🧵[1/4]

New GWAS for intracranial aneurysms, the main cause of subarachnoid hemorrhage (associated with 50% mortality) 👉MVP, FinnGen & previous IA GWAS 👉15,438 cases & 1.2M controls 👉22 loci (5 novel) pointing to genes related to SMCs and pericytes [1/3]

Massive multi-ancestry GWAS resource for 1,167 clinical traits & diseases in 6 global biobanks (n=1,789,365) 👉29,139 locus-trait pairs 👉2,624 non-overlapping loci across the genome 👉associated with 6 traits each (median) 👉colocalization across traits for 72% of loci [1/3]

I find it very interesting that in the 20-year anniversary of the first GWAS hit (CFH for age-related macular degeneration), a new paper uses whole-exome sequencing to uncover a new causal gene in the same locus. Speaks of the challenges of translating genomic signals to causal genes/mechanisms.

This week was the 20th anniversary of the first GWAS that reported a significant finding for a disease trait (age-related macular degeneration). A @nature.com historical lookback on the impact and future of GWAS

We've just posted an updated version of our metabolic trait GWAS preprint. The GWAS summary statistics are still the same as in October, but we've included several new follow-up analyses and completely rewritten the manuscript! See thread below for some highlights. www.medrxiv.org/content/10.1...

Interesting reads on genetics, omics & precision medicine from this week🧬 A 🧵 1⃣ Distribution atlas of the human proteome...

Most genetic variants associated with human disease are assumed to act by influencing gene expression. Expression is regulated at the cell level, but most resources linking variants to expression come from tissue-level data Two advances in the world of single-cell eQTLs🧵 1/9

Analyses of rare genetic variants, especially in coding regions, provide unique insights into causal disease mechanisms—much more straightforward than common variant analyses 🧬 In deCODE (Iceland) and UK Biobank, loss-of-function variants in HECTD2 and AKAP11 were associated with bipolar disorder 🧠

Weekly read list on genetics, multiomics & precision medicine🧵 1⃣ Immune cell-specific gene expression in Asians In 619 Asian donors, scRNAseq-GWAS integration enabled the discovery of molecular immune cell signatures and offered a great resource of single-cell eQTLs 🔗 www.cell.com/cell/fulltex...

Sharing our new paper on rare damaging CCR2 variants that are associated with protection against atherosclerotic cardiovascular disease 🧬 🫀 A short thread about the topline findings🧵

Interesting week reads and resources on human genetics, omics & precision medicine🧵 1⃣From a dog GWAS to a new obesity target! DENND1B variants were the top GWAS signal for obesity in 241 Labrador retrievers—DENND1B variants were also associated with BMI in UK Biobank 🔗 science.org/doi/10.1126/...

A lot to learn from this GWAS of heart failure (HF) & subtypes (153,174 cases, 1,793,175 controls) 👉59 conditionally independent variants across 56 loci 👉exploration of genetic effect heterogeneity across 5 ancestries 👉SNP-based heritability (5.4% for combo HF phenotype) 1/5

Interesting last week reads on human genetics, multiomics & precision medicine🧵 1⃣ Coding & non-coding genetic determinants of circulating proteome Integrating WGS & proteomics, this resource offers genome-wide associations of rare variants with 2,907 proteins 🔗 nature.com/articles/s41...

Dissecting the impact of genetic variation on disease risk by profiling genomics, transcriptomics, proteomics, and metabolomics in the very same 4,732 participants. This is a really rare resource by the INTERVAL study bringing all 4 major omics layers together!

📣 New from the lab: The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes www.nature.com/articles/s41... Check out the INTERVAL RNAseq portal www.intervalrna.org.uk Led by @alextokolyi.bsky.social & Elodie Persyn!

Integrating whole-genome sequencing with proteomics, we now have genome-wide associations of both coding and non-coding rare variants with circulating levels of 2,907 proteins (UK Biobank, n=50,000)❗️🧬

Continuous blood pressure (BP) monitoring is key for diagnosing hypertension and tracking BP-lowering treatments🩸🚑 There's a lot of progress in wearable, cuffless BP sensors with huge potential for deeper arterial phenotyping in clinical and research contexts❗️ I learned a lot from this review👇

Key reads from last week on human genetics, multiomics, and precision medicine 🧵 1⃣New e/sQTL resource from TOPMed In 14,324 whole blood & tissue samples the study detects cis- and trans-e/sQTLs and colocalizes them with 10,000 GWAS signals for 164 traits. 🔗 www.medrxiv.org/content/10.1...

Gene therapy in 4 children (aged 1-2.8 y) with AIPL1-associated severe retinal dystrophy (subretnal injection of rAAV vector comprising human AIPL1) led from legal blindness at birth to significant gains in visual acuity in the treated eye over 3.5 years❗️🧬

How do environmental exposures vs. genetics influence mortality & aging in UK Biobank (N=492,567)🍸🧬 Two key graphs❗️ 1⃣proportion of variance in all-cause mortality explained by exposome vs. polygenic risk score (PRS): exposome adds 17% and PRS 2% on top of age and sex

I would also add UKBB + MVP + FinnGen meta-analysis for a subset of harmonized traits: mvp-ukbb.finngen.fi

Diffusion imaging (MRI) captures early changes associated with cerebral small vessel disease🧠 👉Peak width of skeletonized mean diffusivity (PSMD) is among the most promising biomarkers 👉A new GWAS and ExWAS study explores the genetic architecture of PSMD in N=58,403🧬

Phenome-wide association studies (PheWAS) are a powerful tool for uncovering drug repurposing opportunities and unexpected side effects of novel targets📊 🧬 The best open-access resources for PheWAS analyses👇

A massive genomic exploration of drug targets 🧬💊 👉phenotypic data from UK Biobank, FinnGen, MVP (N>1M) for 2,000 diagnoses 👉gene expression data from GTEx & eQTLGen 👉proteomic data from deCODE, ARIC & Fenland

Spatial proteomics in human carotid atherosclerotic plaques (N=118). A great weekend read❗️ 👉subregions isolated with microdissection (lipid core, fibrous cap, tunica media) 👉mass-spec proteomics 👉proteome-defined subclusters across subregions 👉biological enrichment across subclusters 1/2