The case of GWAS of obesity: does body weight control play by the rules?

Abstract

As yet, genome-wide association studies (GWAS) have not added much to our understanding of the mechanisms of body weight control and of the etiology of obesity. This shortcoming is widely attributed to the complexity of the issues. The appeal of this explanation notwithstanding, we surmise that (i) an oversimplification of the phenotype (namely by the use of crude anthropometric traits) and (ii) a lack of sound concepts of body weight control and, thus, a lack of a clear research focus have impeded better insights most. The idea of searching for polygenetic mechanisms underlying common forms of obesity was born out of the impressive findings made for monogenetic forms of extreme obesity. In the case of common obesity, however, observational studies on normal weight and overweight subjects never provided any strong evidence for a tight internal control of body weight. In addition, empirical studies of weight changes in normal weight and overweight subjects revealed an intra-individual variance that was similar to inter-individual variance suggesting the absence of tight control of body weight. Not least, this lack of coerciveness is reflected by the present obesity epidemic. Finally, data on detailed body composition highlight that body weight is too heterogeneous a phenotype to be controlled as a single entity. In summary GWAS of obesity using crude anthropometric traits have likely been misled by popular heritability estimates that may have been inflated in the first place. To facilitate more robust and useful insights into the mechanisms of internal control of human body weight and, consequently, the genetic basis of obesity, we argue in favor of a broad discussion between scientists from the areas of integrative physiologic and of genomics. This discussion should aim at better conceived studies employing biologically more meaningful phenotypes based on in depth body composition analysis. To advance the scientific community-including the editors of our top journals-needs a re-launch of future GWAS of obesity.

Insights into the multifactorial causation of obesity by integrated genetic and epigenetic analysis

“…Meta‐analyses by the Genetic Investigation of Anthropometric Traits (GIANT) consortium later indicated 941 near‐independent signals from 536 genomic loci to be associated with BMI variability 45, 46 . Conjointly, current GWAS‐identified loci account for approximately 6% of total BMI heritability estimates 47 . Other studies concentrated on WC and WHR because of their interference with body fat distribution and metabolic risk 48 .…”

Reconceptualizing anorexia nervosa

“…Fifth, despite prolonged under‐ or malnutrition and frank cachexia, individuals with acute AN typically do not exhibit sickness behaviors commonly associated with inflammatory processes seen in other somatic and psychiatric illnesses, and only report feeling poorly once renourishment has begun. Finally, weight loss after therapeutic weight restoration (weight relapse) is common as the bodies of individuals with AN appear to be pulled to revert to a low set or settling point even after weight restoration.…”

“…Clinically, it is fairly easy for individuals with obesity to lose weight in the short‐term if they adhere to a ‘diet’, but weight regain is common, and interindividual variability in response to weight loss interventions is considerable . Explanations for weight regain are many and are controversial, but it may reflect a biologically driven process to settle at a previously attained high weight or fat mass . The field has not uniformly conceptualized AN as the opposite of obesity, with constitutional thinness (i.e., underweight, normal eating behavior, desire to gain weight, no cognitive features of AN) typically occupying that position, and showing significant biological differences from AN .…”

“…[53][54][55] Explanations for weight regain are many and are controversial, but it may reflect a biologically driven process to settle at a previously attained high weight or fat mass. 36 The field has not uniformly conceptualized AN as the opposite of obesity, with constitutional thinness (i.e., underweight, normal eating behavior, desire to gain weight, no cognitive features of AN) typically occupying that position, 56,57 and showing significant biological differences from AN. 58 Although early writings proposed that AN might represent a disorder of extreme BMI, 59 we have typically attributed the rapid loss of therapeutically restored weight to psychological or behavioral factors (e.g., purposeful pathological exercise, purging, body dissatisfaction, and drive for thinness).…”

Do we need to re-think the obesity issue?

“…It is obvious that there is need to reconsider the basis of our present understanding of NCDs and to reform the research focus on those issues. Since (i) the epidemiological associations between lifestyle variables (and also other assumed determinants like genes [9]) and obesity are weak, or at best moderate and (ii) treatment and prevention strategies aimed at obesity have rather limited or even no sustained effects [7], there is need to accept that our present view is too narrow to reach solutions. Obviously, we have to keep trying and a solution-oriented approach is wanted.…”