Thread by @doctorveera

Human genetics never ceases to amaze me. It simply blows my mind how exome sequencing at scale leads to such fascinating discoveries. I'll list the things that I loved in this thread.

Disclosure: I work for Regeneron, but I'm not involved in this study.

Here is my favorite plot that I often share in GWAS threads. Note, it took 640,000 exomes to reach sufficient statistical power to discover the large orange dot at the lower left corner, GPR75 the star of the show.

Unlike MC4R where loss of function leads to obesity, with GPR75 loss of function protects against obesity. Look at this beautiful contrast in the distribution of obese and underweight individuals in MC4R lof carriers vs GPR75 lof carriers.

GPR75 and MC4R share many characteristics.
Both belong to the largest family of membrane receptors in humans: GPCRs, which is also "considered the largest family of targets for approved drugs". Here is a pic of rhodopsin (from wikipedia) molpharm.aspetjournals.org/content/93/4/2…

Both MC4R and GPR75 are highly tolerant to lof mutations with pLI=0. The current study reports 46 predicted lof mutations in GPR75.

Both MC4R and GPR75 have a simple transcript structure. Both has only one transcript that is predominantly expressed in brain. MC4R has just only one exon and GPR75 has two (45 of the 46 identified lof variants lie within exon 2)

The authors experimentally demonstrate the lof effect of two variants that were most frequent (seen at least in 10 individuals).

In vitro experiments show that these variants result in cellular retention i.e the truncated proteins fail to reach the plasma membrane and accumulate inside the cell. Beautiful!

Knocking out GPR75 in mice leads to an impressive resistance to high fat diet induced weight gain. Not just that, the mice is also resistant to metabolic effects of HFD like glucose and insulin impairments.

The authors find protective associations with lipid and diabetes traits in humans, but they are not statistically significant. This is a nice example to appreciate the relationship between sample size, allele frequency, proximity of the phenotype to DNA and environmental effects.

Note here it's likely the BMI is proximal but the metabolic effects are distal to GPR75. Also considering the strong environmental influences on diabetes and lipid traits, detecting a statistically significant associations in humans will require extremely large sample sizes.

There are also other fascinating findings in this paper who were lost in the shadow of GPR75 findings and got minimal attention.

One of the cohorts analyzed in this paper is MCPS, which comprise of ~96k Admixed Americans from Mexico city, which houses one of the most obese populations of the world (>36.1% of adults were obese in 2018)
thelancet.com/journals/landi…

So, obviously these individuals should be enriched for obesity related genetic mutations. The authors identified a lof missense variant in MC4R that is present 1% of the admixed Americans in Mexico, but rare elsewhere in the world.

More importantly, the prevalence of this variant raises from 1% to 3% when considering only the obese individuals suggesting MC4R deficiency is a major cause of obesity in this population.

I particularly like this paragraph. There were 17 individuals who were homozygous for this variant and none of them were normal weight, suggesting that that "homozygous MC4R deficiency might be incompatible with the maintenance of a healthy weight"

And one last finding that requires highlight is the famous FTO locus, a classic example where a GWAS variant is linked to a distal effector gene via chromatin looping.

cell.com/cell-metabolis…

Even after sequencing 640k exomes, there seems to be no evidence for rare variant associations with FTO or IRX3 or IRX5. So, if at all there are any rare variants associations here, they are likely not large, otherwise the current analysis would have detected it.

So, my take way here is, though rare variants more often pinpoint causal genes at common variants identified GWAS loci, it's not always the case. FTO locus is a good example.

Overall this is a hardcore genetics paper and perhaps a landmark discovery in the history of obesity genetics. Don't miss it. Read and enjoy the science :) Congratulation to all the authors on this impressive paper.