Thread by @skathire

A predicted null mutation which protects against *obesity*
And the gene is a G-protein coupled receptor expressed highly in habenula!!

"Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease"

Read here: rdcu.be/MrQa

and team analyzed 3,759 DNA sequence variants predicted to lead to loss of protein function against 24 traits and diseases in @uk_biobank to find:
18 new low-frequency or rare variants associated with traits/diseases
rdcu.be/MrQa

We found 4 null, protective mutation results to be particularly interesting:
1. GPR151 and BMI
2. IL33 and asthma
3. IFIH1 and autoimmune disorders
4. PDE3B and body fat distribution

Loss-of-function variant (p.Arg95Ter) GPR151 & protection against BMI, type 2 diabetes, & CAD.
*expression limited to CNS
*lineage tracing neurons expressing GRP151, connections to hypothalamic neurons, region important in control appetite
rdcu.be/MrQa

IL33 splice site variant (carried by 1 in 125 people) and robust protection against asthma.
*suggestive evidence for other atopic diseases including *food allergy*
*mAb targeting IL33 in development for asthma
rdcu.be/MrQa

IFIH1 loss-of-function variants protect against a range of autoimmune diseases.

Initially shown for T1D by John Todd a few years ago. Now, we see signal for other diseases including hypothyroidism
rdcu.be/MrQa

Finally, phosphodiesterase 3B null mutation leads to:
1. improved body fat distribution
2. lower risk for hypercholesterolemia
3. protection against CAD (nominal significance)
Of note, PDE3B the target of the FDA approved drug cilostazol
rdcu.be/MrQa

Scanning for null mutations which protect against disease proving useful strategy to:
1. identity new targets for therapy
2. anticipate efficacy of inhibition
3. identify full range of potential indications
rdcu.be/MrQa

IMO, key ingredients for protective mutation scanning strategy:
1. open data resource (eg @uk_biobank)
2. genotypes, rich set of phenotypes
3. clever people who understand medicine and statistical genetics (eg @connoremdin @amitvkhera)

Finally, want to give a huge shoutout to @connoremdin the lead author and current 2nd year student @harvardmed

Quite a productive couple of years in medical school so far. 👇😳👏

Can't wait to see what future holds