Is there a major gene for obesity?

Several large population studies using segregation techniques predicted the existence of one or more ‘major’ recessive gene effects independent of the discovery of any specific obesity gene (Rice et al.,  1996;  Borecki et al.,  1998).  Studies based on candidate genes or obesity syndromes have reported concentration of mutations thought capable of contributing to the obese phenotype amongst the obese population at large.

Segregation studies
Segregation studies test the hypothesis that there exist one or more (uncharacterized)  recessive genes with major effects on a specific obesity phenotype.

Support for a putative large (recessively inherited) genetic component of obesity was initially suggested by observations that the obese proband in many studies often demonstrates a far greater degree of obesity than either their parents or siblings. If it is hypothesized that the parents carry heterozygous mutations, one would expect that the frequency of transmission of a recessive allele from a homozygous dominant, homozygous recessive or heterozygous parent would be close to 0, 100 and 50 per cent, respectively. Evidence for one or more major recessive genes accounting for some 45 per cent of the variance in fat mass being so transmitted has been reported in 6 per cent of individuals in one study population (Rice et al., 1993). In addition, reports of major gene effects accounting for some 37–42 per cent of the variance in regional fat distribution have raised the intriguing possibility of one major gene effect subtending total and visceral fat accumulation with another influencing subcutaneous fat topography elsewhere (Bouchard et al., 1998).

It has been suggested recently that 2.9 per cent of the general obese population are heterozygotes for at least one of the six autosomal recessive genetic defects present in BBS (Croft et al.,  1995)  and mutations in the gene coding for the MC-4 receptor may be present in up to 4 per cent of the obese (Vaisse et al., 2000). However, it remains to be seen whether these mutations are biologically important in the sense of leading to alterations in protein function and their true significance is currently debated (Jacobson et al., 2002).

Warden CH and Fisler JS
Katsanis N, Beales PL, Woods MO

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