Thread by @skathire

👇🏽 what I hope will be our most impactful discovery to date

An enzyme whose loss of function lowers blood cholesterol & *protects* against fatty liver & cirrhosis

Kudos to @connoremdin whose clever analysis of public data (@ukbiobank) led to observation

biorxiv.org/content/10.110…

Here's the story of the discovery:

@connoremdin noticed that gene variants affect cirrhosis in same direction, similar effect size regardless of underlying etiology (fatty liver, alcohol, viral)

And so, idea: combine all causes of cirrhosis into a single new case definition and perform genetic analysis

Genome-wide association for all-cause cirrhosis in five cohorts with 3754 cirrhosis cases and 444830 controls:

New discovery: common coding variant in the MARC1 gene associates with *lower* cirrhosis risk

All the positive controls show up as top results as well.

MARC1 is an enzyme (Mitochondrial Amidoxime Reducing Component 1 gene)

Is the protection from cirrhosis due to gain or loss of enzyme function?

Got lucky here: there is a stop codon in MARC1 carried by about 1 in 5000 in @uk_biobank!

And stop mutation carriers 👇🏽

And wouldn't you know it, back in 2010, we had shown that MARC1 (labeled with alternative name MOSC1 here) genetic variation affects plasma cholesterol

(MARC1 A165T)

T allele that lowers risk for cirrhosis also *lowers* blood biomarkers

1. lower blood LDL cholesterol
2. lower blood total cholesterol
3. lower blood ALT

(MARC1 A165T)

T allele that lowers risk for cirrhosis, lowers blood biomarkers,

also *lower fatty liver* on hepatic CT and physician-diagnosed fatty liver.

So, in summary MARC1:
1. enzyme
2. loss of function protects against cirrhosis
3. loss of function lowers blood cholesterol, ALT, lower fatty liver
4. expressed in liver and adipocytes

What is the function of MARC1? Let's all figure this out!
biorxiv.org/content/10.110…

And a key takeaway for me:

These days, for cool new human genetics observations,

it’s less about the genetic data
and
more about the analyst

Thx @connoremdin & @maryehaas