1/Prevalence and expressivity of loss of function mutations in the Melanocortin 4 Receptor (MC4R) in a UK birth cohort medRxiv 2020.10.30.20220467. Delighted to report that our work done in ALSPAC in collab. with @mrc_IEU @nic_timpson @KaitlinWade is now out in preprint form/
2/The gene is an "old friend" but the results are remarkable i) Its a representative birth cohort & all muts functionally studied so we're able to establish the prevalence of functionally impaired het. muts at ~1/330 i.e. =200,000 ppl in UK (predict 1M in USA if freq. similar)
3/ ii) By age 18 ppl with these mutations on avg. carry ~17.8kg extra weight! (15kgs of which is fat!) Much bigger impact than conferred by the top end of the polygenic risk score.
iii) Comparable mutations in UKBB participants have much lower impact. Why?
iii) Comparable mutations in UKBB participants have much lower impact. Why?
4/Most likely explanation is that people v. obese from childhd. are less likely to volunteer for UKBB. This is supported by previous studies revealing "healthy" bias in UKBB. Its a great study, just need to be careful about interpretation when dealing with phenotypes like obesity
5/ So. Heterozygous, loss of function, MC4R mutations seem to be more common and have a bigger impact on weight than previously suggested. Big unmet therapeutic need. Thanks to the gang at @MRC Metabolic Diseases Unit @MRL_Cam including @brianlamx @GilesYeo and Audrey Melvin
6/Thanks to Warren Pan now back in U Mich. who kicked this off during his MPhil., to @wellcometrust who provided the funding for the pooled sequencing methodology development and @The_MRC for the rest of the work
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