• Alzheimer Europe

• Nature paper: Examining the role of common variants in rare neurodevelopmental conditions
• Genes and Health Project

• Focusing on recent findings related to Huntington’s HTT repeat expansion in striatal neurons
• Leveraging newly-sequenced GWAS data from the UK Biobank and All of Us cohorts to study short tandem repeats (STRs), particularly the CAG triplet repeat
• Identifying multiple participants with expanded repeats exceeding 45 base pairs, revealing that three genetic sites account for over 97% of these expansions
• Exploring factors that may prevent or impact the phenotypic manifestation of repeat expansions
• Read the paper

• Investigating how different haplotypes interact with low-density lipoprotein receptors in neuronal tissues, influencing cholesterol lipid transport and AD risk
• Examining lipid profiles in APOE carriers, including elevated low-density lipoprotein cholesterol levels in APOE4 carriers and decreased levels in APOE2 carriers, and their effects on cholesterol and nutrient supply to neurons
• Exploring gene therapy approaches for delivering APOE2 into the brain
• Read the paper

• Exploring the relationship between age of menopause and ovarian function
• Addressing the challenges in studying recessive genetic associations
• Examining how homozygosity of a variant in the CCDC201 gene influences primary ovarian insufficiency and strongly associates with early menopause
• Read the paper

• Examining the 72% participation rate among invited families and the 90% consent rate for expanded panel screening
• Exploring opportunities for early treatment and preventive interventions
• Ensuring databases are representative across diverse populations
• Tune into Episode 117 to hear from the leader of the GUARDIAN program, Wendy Chung

• “~83% of random promoter sequences yielded measurable expression” - de Boer CG, Nat Biotechnol, 2020
• “Recently evolved enhancers are formed predominantly by exaptation of ancestral DNA” - Villar D, Cell, 2015
• “Extensive co-regulation of neighboring genes complicates the use of eQTLs in target gene prioritization” - Tambets R, et al., HGG Adv., 2024

• “eQTLs at GWAS loci are more likely to point to genes with low enhancer redundancy not associated with disease” - Wang X, Goldstein DB, Am J Hum Genet., 2020
• “GWAS and eQTL studies are systematically biased toward different types of variants” - Mostafavi H, et al., Nat Genet., 2023
• “CNVs are buffered by post-transcriptional regulation in 23%-33% of proteins significantly enriched in protein complex members” - Gonçalves E, et al., Cell Systems, 2017

• “cis-eQTL target genes are relatively poor indicators of ‘true positive’ causal genes” - Stacey D, et al., NAR., 2018
• “When molecular QTL colocalization evidence was removed, we saw similar classification results” - Mountjoy E, et al., Nat Genet., 2021
• “Key predictive features included coding or transcript-altering SNVs, distance to gene, and open chromatin-based metrics” - Forgetta V, et al., Hum Genet., 2022

• Veera’s Substack Post: How a Jumping Gene Shaped Human Skin Color Evolution - https://www.gwasstories.com/p/how-a-jumping-gene-shaped-the-human
• Original Research: Study by Dr. Po-Ru Loh and Dr. Steve McCarroll from the Broad Institute, published in Nature Genetics - https://www.nature.com/articles/s41588-024-01841-4

• Veera’s Substack Post: The Big Tau: A New Hope for Alzheimer’s - https://www.gwasstories.com/p/the-big-tau-a-new-hope-for-alzheimers
• Original Research: Study from Dr. Huda Zoghbi’s lab on how the big tau splice isoform resists Alzheimer’s-related pathological changes - https://www.biorxiv.org/content/10.1101/2024.07.30.605685v1

• Veera’s Substack Post: Discovery of TMEFF1, a viral restriction factor in the human brain - https://www.gwasstories.com/p/discovery-of-tmeff1-a-viral-restriction
• Original Research: Study by the Jean-Laurent Casanova Lab at Rockefeller University, Human TMEFF1 is a restriction factor for herpes simplex virus in the brain - https://www.nature.com/articles/s41586-024-07745-x

• Veera’s Substack Post: De novo enhancer creation by a noncoding mutation - https://www.gwasstories.com/p/de-novo-enhancer-creation-by-a-noncoding
• Original Research: A novel familial cardiac arrhythmia syndrome with widespread ST-segment depression. The authors note, “We believe this is the first description of an entirely de novo cryptic enhancer causing a Mendelian disorder.” - https://www.nejm.org/doi/full/10.1056/NEJMc1807668

• Veera’s Substack Post: Genomes vs. Exomes - https://www.gwasstories.com/p/genomes-vs-exomes
• Original Research: Yield of genetic association signals from genomes, exomes and imputation in the UK Biobank - https://www.nature.com/articles/s41588-024-01930-4

• Foundations of Genetics and Genomics
• Fundamentals of Data Science in Precision Medicine and Cloud Computing
• Fundamentals of AI/ML in Precision Medicine

• This pathogenic variant escaped notice for years because it was not located in a protein coding region of the genome
• It now shows potential as a target for various therapeutic developments for children with developmental disorders 
• See the original paper here: De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders

• Direct interactions with the LRRK2 gene through its armadillo domain, resulting in a gain of function missense mutation
• How RAB32 was discovered as a significant mutation in PD research
• The strong therapeutic implications of RAB32 and LRRK2
• See original papers: RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses and Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease

• Making discoveries by following a biological thread, a rare privilege enjoyed by few fields like immunology
• See original paper here: Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus
• A related paper from two years ago on SLE and the TLR7 gene: TLR7 gain-of-function genetic variation causes human lupus

• Redefining research goals to make better sense of old discoveries, in addition to making new discoveries
• deCODE’s previous work on the homozygosity deficit inference 
• APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease
• Homozygosity for R47H in TREM2 and the Risk of Alzheimer’s Disease

• Genome-scale metabolic reconstruction of 7,302 human microorganisms for personalized medicine
• APOLLO: A genome-scale metabolic reconstruction resource of 247,092 diverse human microbes spanning multiple continents, age groups, and body sites

• Towards personalized genome-scale modeling of inborn errors of metabolism for systems medicine applications

• Webinar: Participant Diversity: Increasing the Impact of Biomedical Research Webinar

• Reference Guide: Closing the gap in patient data for black and south Asian communities

• Paper: Unpacking race and ethnicity in African genomics research

• Reference paper: Conflating race and ancestry: Tracing
  decision points about population descriptors over the precision medicine research life course

• The importance of low-affinity binding between transcription factors and targets 
• How these lessons can help us improve our understanding of drug and target discovery 
• See Veera’s January round-up for more information: https://www.gwasstories.com/p/january-2024-human-genetics-roundup

• An overview of the roles lncRNA play in the human genome
• The discovery of a lncRNA deletion that is linked to a CDH2-mediated neurodevelopmental disorder
• Insights into Angelman syndrome and a therapeutic design currently being used to treat it
• See Veera’s February Roundup for more information: https://www.gwasstories.com/p/february-2024-human-genetics-roundup
• Twitter thread from the original author of the study: https://twitter.com/VGaneshMDPhD/status/1755708315181744330

• See Veera’s January Roundup for more information: https://www.gwasstories.com/p/january-2024-human-genetics-roundup)

• A recent massive GWAS on type 2 diabetes clustering the variants of disease mechanisms 
• A recent paper published in Nature Medicine that shows differences in the lipodystrophy clusters between East Asians and Europeans: https://www.nature.com/articles/s41591-024-02865-3
• How type 2 diabetes manifests differently across ethnic groups, potentially influencing personalised treatment strategies

• A Systematic Study of Unsaturation in Lipid Nanoparticles Leads to Improved mRNA Transfection In Vivo
• On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles
• Selective ORgan Targeting (SORT) nanoparticles for tissue specific mRNA delivery and CRISPR/Cas gene editing
• Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models

• A major genetic risk factor of stroke has been identified in South Asian communities. 
• The first ever large-scale study to explore South Asian genetics.
• For the first time, the effect of consanguinity on the risk of common diseases is studied in British Pakistanis and Bangladeshis. 

• The ‘low-hanging fruit’ discovered earlier in the GWAS timeline, requiring just a few hundred participants. 
• An early-breaking story in Nature explores the underlying link between GDF15 (a hormone that is elevated during pregnancy) and a pregnancy-associated medical condition characterised by severe nausea.
• Genome-Wide Association Studies (GWAS) of Reynaud’s phenomenon have been reported by two independent teams, who uncovered a strong signal near ADRA2A.

• Momentum continues for rare variant discoveries based on UK biobank exome sequencing.
• Gene BSN (Bassoon) continues to fascinate in 2023, as it’s discovered that it likely plays a key role in neurodegeneration.
• In the world of non-coding variants, FOXA2 non-coding deletions are found to cause congenital hyperinsulinism and the loss of ZNF808 results in aberrant activation of silent transposons.

• Paper from Decode quantifies the impressive mutation rate of STRs, which will put the de novo mutation rate of other variants to shame. 
• Paper from Po Ru Loh’s group shows that for two of the GWAS loci discovered early in the timeline, the causal variant is likely VNTRs.
• A story from ASHG on Huntington highlights a major advancement in the understanding of HTT repeat-mediated neurodegeneration.

• The new and old genetic discoveries being translated into medicines.
• A 25-year-old genetic puzzle that’s been solved using long-read sequencing.
• Innovations in phenotyping and quantifying cellular phenotypes using microscopy.
• Using discarded embryos to run genetic associations. 

• Publication in Nature Genetics: Rare coding variants in CHRNB2 reduce the likelihood of smoking, an exome-wide association study identifying rare coding variants in CHRNB2 that may reduce the likelihood of smoking.
• Designing cover art 
• Genetic links to neural circuits and their role in addiction

• A milestone year in GWAS-driven drug development: FDA Approval of Casgevy, a cell based gene therapy for the BCL11A transcription factor, in the US and UK to treat sickle cell disease 
• Strong genetic support for the ongoing development of APOL1 inhibitors to treat kidney disease
• Additional disease modifier variants, including the APOE4 variant in Alzhemer’s Disease

• Looping back to BCL11A: how neurodevelopmental disorder patients with BCL11A haploinsufficiency provided insights into sickle cell treatment
• BCL11A knockdown to induce fetal hemoglobin production and alleviate sickle cell disease
• Recessive mutations in HMGCR provide the missing link into why statins can induce myopathy. Learn more in this Atlantic article.
• The often underappreciated importance of studying rare Mendelian diseases

• Why are pharmaceutical companies studying rare variants?
• How the FTO locus associated with obesity highlights challenges in identifying causal gene variants
• Surprising twists in translating mice physiology to human physiology, and decades-long quest to understanding the mechanism behind this extremely early GWAS hit

• The rise of large-scale studies looking beyond European populations
• The FinnGen study: a significant step forward in understanding the genetic basis of diseases in founder populations
• Interesting discoveries from integrating non-European populations in biobanks and Direct to Consumer databases
• A recent 23andMe paper that identifies a founder variant in Puerto Rican populations associated with a strong risk effect on cataract development 

In this podcast, CEO and Co-founder Dr Patrick Short discusses the personalised genomics industry, as well as his journey from PhD to founder and some important lessons he learnt along the way.

1) 23andMe’s plan to start collecting health data

2) New research that’s sounding alarm bells about the accuracy of genotyping tests

3) The largest-ever study of genetics and PTSD 

4) A new $160 million round of funding for a SanFrancisco-based company working on the early detection of cancer

5) A breakthrough cure for another rare disease, amyloidosis, that’s just been approved in the UK

1) How reliable is the DNA testing offered by sites like Ancestry.com or 23andMe?

2) Does DNA testing for diet and fitness really work?

3) Does 23andMe provide accurate results for people of Indian heritage?

4) How much of the genome does 23andMe sequence? Can their data be used to study disease?

5) How seriously would you take the DNA ancestry and health reports from a place like 23andMe?

Quite possibly, but one thing's for sure, his company (dnatestingchoice.com) know a thing or two about a good DNA test.

This fascinating discussion with Craig Macpherson explores the start of direct to consumer DNA testing, why these companies are so successful. As well as his thoughts on ancestry testing, current practices around data privacy and the future of genetic testing.