Thread by @jonasbovijn

🚨 Publication alert: largest to date multiancestry exome analysis of body fat distribution discovers INHBE mutations associated with favorable adiposity and PROTECTION from diabetes! 🚨

Out today in @NatureComms

👇🧵 key takeaways below…

nature.com/articles/s4146…

Fat distribution: MAJOR BUT OVERLOOKED risk factor for diabetes & heart attacks globally

Storing⬆️fat in waist and⬇️in hips gives ⬆️⬆️⬆️risk – independent of overall body fat (👇)

🚨Lots of drug development in obesity; almost none for fat distribution

nature.com/articles/s4146…

Fat distribution is partly in our 🧬

nature.com/articles/s4146…

#exome #diabetes #obesity #NASH

Mutations in fat tissue genes ➡️ lipodystrophies

⬇️fat but⬆️diabetes

Counterintuitive but, calories not stored in adipose end up in liver, circulation (hyperlipidemia) & other undesirable places

academic.oup.com/edrv/article/3…
rcpjournals.org/content/clinme…

@StephenORahilly @DanielJDrucker

#GWAS ➡️ 100s common variants, often at adipose genes

nature.com/articles/natur…
jamanetwork.com/journals/jama/…
academic.oup.com/hmg/article/28…
nature.com/articles/s4146…

@amitvkhera @ceclindgren @saralpulit @saaket_agrawal

Inability to expand adipose to store excess calories➡️diabetes, 🫀 disease

Genetically⬆️WHR ➡️diabetes, 🫀 disease

diabetesjournals.org/diabetes/artic…
jamanetwork.com/journals/jama/…
nature.com/articles/ng.37…

@connoremdin @skathire @sguyenet @markmccarthyoxf @ethanjweiss @YaghootkarH @timfrayling

Note:

Mechanisms leading to ⬆️WHR

via ⬆️waist fat (abdominal obesity) OR
via ⬇️hip fat (subtle partial lipodystrophy)

can be distinct AND

both associated with ⬆️cardiometabolic risk

jamanetwork.com/journals/jama/…

Can we find possible new targets to ⬇️ this risk? 💉💊

Exome sequencing + 100,000s 👫+
multiple ancestries (diversity of 🧬 & environment)
= Proven recipe for new gene discovery

PROTECTIVE mutations ➡️ possible targets for therapy

It works!
science.org/doi/10.1126/sc…
nature.com/articles/s4158…
nejm.org/doi/full/10.10…

We analyzed exomes from >618,000 👫 of 5 ancestries from 🇬🇧🇲🇽🇸🇪

Largest & most ancestrally-diverse analysis for fat distribution thanks to @UIME_UNAM @Oxford_NDPH @GeisingerRsrch @lunduniversity @uk_biobank

➡️16 genes with rare coding variants associated with fat distribution

Discovered genes are enriched for:

➡️Mendelian lipodystrophy genes (PPARG, PLIN1)
➡️Genes expressed in ADIPOSE = critical energy-storing tissue

Association effects are:

➡️6-fold > than common variants
➡️Often stronger in women than men

⚡️ Rare mutations in liver-expressed INHBE associated with

➡️favorable fat distribution (lower WHR, larger hips)

➡️favorable metabolic profile (lower liver enzymes, lower triglycerides, lower HbA1c)

➡️~28% lower risk of type 2 diabetes!

Highlights & insights:

1⃣Dozens of rare coding variants with large effect on fat distribution

2⃣Enriched for lipodystrophy genes, adipose genes

3⃣INHBE LOF➡️favorable adiposity and diabetes protection➡️possible therapeutic target

And MORE – full story: nature.com/articles/s4146…