31 May 2021

The Genetics Of Height And Weight In Hispanics

Height and weight have important environmental influences. Diet quality influences height at a population level. Similarly, the transition from traditional diets and active lives to modern diets and sedentary lives driving higher body mass index (BMI) levels for entire populations. But, controlling for diet and exercise, height and BMI are strongly genetic in character, as is the most subtle detail known as BMI-adjusted waist-to-hip ratio (WHRadjBMI).

Some of the relevant genes are common in many populations, but some genes relevant to these traits are found predominantly in specific ancestral populations, or are more notable there.

A new study (bioRxiv preprint here) by the HISLA consortium did an analysis of a large sample of Hispanic/Latino individuals (N=69,105) pooled from eighteen different genome studies to try to identify genes relevant to these traits. This is what they found:

[W]e discovered one novel BMI locus, two novel signals in established loci for BMI, and one secondary signal in an established locus for height. In our trans-ethnic meta-analysis, we identified three additional novel BMI loci, one novel height locus, and one novel WHRadjBMI locus. We also identified three secondary signals for BMI, 29 for height, and two for WHRadjBMI. We replicated 64 established anthropometric loci in Hispanic/Latino populations at genome-wide significance (28% of previously-reported index SNP anthropometric associations).
Identifying relevant genetic loci associated with these phenotypes, in addition to making it possible to construct a genetic risk index for individuals, also helps us to understand the biochemical mechanics of height, weight and waist-to-hip ratios, and to make educated guesses about the historical selective fitness factors that shaped modern genomes for these traits. This understanding can help us determine what approaches are and are not likely to be successful in reducing stunted growth and regulating weight in modern populations.

The large sample size makes it possible to identify genes with smaller effect sizes with statistical significance, while reducing the risk of false positive gene identifications.

The introduction to the paper provides interesting and notable context:
A complex interplay between political, social, and economic factors has led to an increasing obesogenic global environment.
In this modern context, many low- to middle- income nations have experienced a rapid transition from under-nutrition and growth stunting to overnutrition and obesity. Moreover, population-based surveys from 1975-2002 show that there is an inverse ecologic relationship between the prevalence of growth stunting and the prevalence of overweight seen among preschool children (0-5 years of age) in Latin America. Growth stunting of preschool children ranges from relatively rare (7%) in the Caribbean to notably common (20%) in Central America. Moreover, it is a risk factor for overweight/obesity independent of a child’s socioeconomic status. 
In Latin America, 35% of the total population was overweight and another 23% was living with obesity by 2016. In Mexico, more than 71% of adults are currently overweight; it is projected that by 2050 only 12% of men and 9% of women will have a healthy weight. And, in a recent study in Argentina, Chile, and Uruguay, the prevalence of obesity was 36%, but when using waist circumference as a measure of central obesity, it was far higher (53%). Within each of these populations, there are also disparities by sex and education. 
Race, ethnicity, and ancestry may play a role in anthropometric-related health disparities in Latin American. Previous studies have described the historical contexts leading to admixture in Latin American populations as characterized by highly diverse (variable) ancestral proportions from any of the following regions: the Americas, Europe, Africa and East Asia. 
In fact, proportion of Native American ancestry is associated with numerous biomedical traits, like obesity-related traits, and is most strongly associated with height. Height is inversely associated with proportion of Native American ancestry, even after taking into account the fact that globally over time populations have become taller due to mainly non-genetic nutritional factors. 
The ultimate drivers of this association remain to be elucidated; it is possible that genetic factors and/or socio-economic factors strongly associated with Native American ancestry could be responsible for these findings. Recent studies are starting to provide relevant insights on this topic. 
As an example, a recent genome-wide association study in Peru19 identified a missense variant in the FBN1 gene (rs200342067) that has the largest effect size so far described for common height-associated variants in human populations (each copy of the minor allele reduces height by 2.2 cm). In the 1000 Genomes Project samples, rs200342067 is only present in two American samples (MXL: 0.78% and PEL: 4.12%), and yet the authors reported that this missense variant shows subtle evidence of positive selection in the Peruvian population. 
Obesity in Latin America has quickly surpassed the levels previously seen only among adults of high-income nations, like Canada and the United States (US). In Canada the number of people reporting Latin American origins grew by 83% from the 2001 census relative to the 2016 census, representing 1.3% of the total Canadian population. In the US, both the population size and diversity in national origins (backgrounds) of US Hispanic/Latinos have been increasing over the past several decades. If past demographic trends continue, 24% of the US adult population will identify as Hispanic/Latino by 2065. 
Obesity-related financial costs in the US are projected to double every decade to ~$900 billion by 2030. US Hispanic/Latino adults and their children/adolescents face a greater burden of obesity than their non-Hispanic white counterparts.  

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