1 / Zhao et al, ‘Population scale whole genome sequencing provides novel insights into cardiometabolic health’  MedRxiv (2024)

This collaborative work with GSK was one of the first to demonstrate the power of whole genome sequencing over exome sequencing in the analysis of large-scale population studies. The study identified loss of function variants in several genes substantially increasing the risk of T2D and obesity, highlighting a new mechanism linking glucose homeostasis to kidney function via IRS2 function. (link)

2 / Kentistou et al, ‘Understanding the genetic complexity of puberty timing across the allele frequency spectrum' Nature Genetics (2024)

This is the largest study to date focussing on the discovery of genetic determinants of pubertal timing, identifying > 1000 genomic loci in 800,000+ genotyped women. Identified genes cumulatively, and in some cases individually, have large effects that predict individuals in clinical extremes. Identified genes highlight novel biological pathways and suggest a new hypothesis that the ovarian reserve might signal centrally to trigger puberty. (link)

3 / Zhao et al, ‘Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease’ Nature Genetics (2024)

This large-scale exome sequencing study was performed in collaboration with AstraZeneca and demonstrates that loss of function variants in BSN lead to a six-fold increase in the risk of obesity, alongside large effects on T2D and fatty liver disease.

This is one of the largest genetic risk factors for these diseases identified to date, highlighting a novel biological mechanism implicating degenerative neuronal processes in the aetiology of obesity (link)

4 / Kaisinger et al, ‘Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity’
Cell Genomics (2023)

This was the first large-scale exome sequencing study to date to identify rare protein-coding variants conferring sex-specific risk of obesity. It implicated loss of function variants in apoptosis gene DIDO1 with obesity and more broadly highlighted the link between DNA damage response genes and metabolism (link)

5 / Gardner et al, ‘Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the aetiology of type 2 diabetes’ Cell Genomics (2022)

The largest T2D exome sequencing study to date (~450,000 individuals), identifying a number of genes where rare protein coding variants confer large risk of developing T2D. We also use both common and rare variant approaches to directly implicate

IGF1 resistance in T2D pathogenesis. (link)

6 / Lam et al, ‘MC3R links nutritional state to childhood growth and the timing of puberty’ Nature (2021)

Here we use a range of population genetic, clinical, animal and cellular models to demonstrate that MC3R is responsible for communicating metabolic status to the brain to regulate the timing of sexual maturation, the rate of linear growth and the accrual of lean mass. (link)

7 / Zhao et al, ‘GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health' 
Nature Communications (2021)

One of the first papers to demonstrate that GIGYF1 loss of function is associated with a ~6 fold increased risk of type 2 diabetes, greater than any effect previously described for the disease. (link)

8 / Ruth et al, ‘Using human genetics to understand the disease impacts of testosterone in men and women’ 
Nature Medicine (2020)

This project identified nearly all known genetic determinants of circulating testosterone to date. We use these genetics findings to demonstrate that increased testosterone levels are causally beneficial for male metabolic health (predicting the outcome of a subsequent clinical trial), but deleterious for women's metabolic health. (link)

9 / Warrington et al, ‘Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors’ Nature Genetics (2019)

This was the largest genetic study of birth weight when published, identifying 190 genetic determinants. The major advance in this paper was the ability to distinguish between maternal and fetal effects, which we use to identify modifiable risk factors in mothers for low birth weight. (link)

11 / Day et al, ‘Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk'. Nature Genetics (2017)

The largest genetic study for puberty timing when published, identifying ~400 genetic determinants in ~370,000 genotyped women. This was the first paper to demonstrate a robust causal link between puberty timing and cancer susceptibility using genetics. It also demonstrated a bi-directional relationship between puberty and obesity for the first time - obesity in children promotes earlier puberty, whilst earlier puberty is itself an independent risk factor for later life obesity. (link)

12 / Horikoshi et al, ‘Genome-wide associations for birth weight and correlation with adult disease’ Nature (2016)

This study was the first to demonstrate that the well documented epidemiological link between low birth weight and later life risk of cardiometabolic disease is likely largely explained by inherited [pleiotropic] genetic effects, rather than in utero programming (link)

13 / Perry et al, ‘Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche‘ 
Nature (2014)

When published this was the largest genetic analysis ever performed in women and the first to demonstrate that puberty timing was a target of genomic imprinting. This work led to several later theories about the nature of how genomic imprinting evolved in humans. (link)

14 / Perry et al, 'Stratifying type 2 Diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases' PLoS Genetics (2012)

The identification of T2D associated variants in LAMA1 was the first example of a genetic effect that was only present in a

sub-group of T2D patients with low BMI. This observation suggested there may be sub-groups of T2D patients with a different underlying aetiology. (link)

15 / Frayling et al, ‘A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity’ Science (2007)

Identification of the first common genetic determinants of obesity and one of the most highly cited papers in human genetics.

Not a project I led, but something I really enjoyed working on that helped shape my thinking in this area. (link)