Chipping away the 'missing heritability': GIANT steps forward in the molecular elucidation of obesity - but still lots to go.
Although heritability of human body weight is assumed to be high, only a small fraction of the variance can as yet be attributed to molecular genetic factors. Single monogenic forms of obesity have been identified. Functionally relevant coding mutations in the melanocortin-4 receptor gene occur in 1-6% of extremely obese children and adolescents and thus represent the most common major gene effect. Genome-wide association studies (GWAS) had previously identified 14 obesity loci with genome-wide significant (p < 5 x 10-8) associations. Many of the respective genes are expressed in the central nervous system. The GIANT (Genetic Investigation of ANtropometric Traits) Consortium has now performed a meta-analysis of GWAS data based on 123,865 individuals of European ancestry followed by confirmatory analyses for the 42 best independent loci in up to 125,931 independent individuals (Speliotes et al: Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nature Genetics; epub October 2010 [1]). Apart from confirming the 14 known loci, 18 novel BMI-associated loci (p < 5 x 10-8) were identified. Several of the new loci point to genes involved in key hypothalamic pathways of energy balance. The identified variants mostly have small to very small effect sizes; only 1-2% of the BMI variance is explained. Currently, a consensus explanation for this 'missing heritability' in complex diseases has not yet emerged.
Hebebrand
Johannes
J
Department of Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany.
Volckmar
Anna-Lena
AL
Knoll
Nadja
N
Hinney
Anke
A
D000293:Adolescent; D000328:Adult; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics*; D002648:Child; D005060:Europe; D019317:Evidence-Based Medicine; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D040941:Heredity; D006801:Humans; D015201:Meta-Analysis as Topic; D009765:Obesity / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D044465:White People / Q000235:genetics*