Genetic variants associated with a birth weight-lowering effect in other populations, near CCNL1 or in ADCY5 locus are not associated with birth weight in this Indian cohort, but the ‘birth weight-lowering’ variant of ADCY5 was associated with raised glucose and reduced early phase insulin secretion.
The Indian birth weight is generally about 0.8 kg less compared to the West 
, and the mean birth weight in our cohort was 2.8 kg. Not only was there any modulation between genotypes at this lower level, the gene frequencies of the ‘birth weight-lowering’ variants in ADCY5
and near CCNL
were also the same (ADCY5
) or lower (CCNL
) than in the original report in Europeans 
. The absence of an association between ‘birth weight-lowering’ genetic variants and birth weight is therefore likely to be attributed to strong environmental influences which dominate over the genetic effects. This would be supported by the observations of slightly higher birth weights in Indian immigrants in the West compared to the native Indian babies 
. The existence of other genetic variants influencing birth weight in the Indian setting is possible, but rather unlikely considering the considerable genetic diversity in India 
contrasted with the uniformity in the low birth weight phenotype.
variant has been associated with increased plasma fasting glucose at a genome-wide level 
and it appears that, type 2 diabetes genes in general are reproduced in Indians 
. In the current study, rs9883204 variant of ADCY5
was associated with raised fasting and 2-hour glucose concentrations following an oral glucose tolerance test performed in early adulthood. Although this finding would be in general agreement with the fetal-insulin hypothesis, it is paradoxical compared to a recent study in a large Danish cohort as another ‘birth weight-lowering’ (rs11708067) variant was associated with reduced adult insulin resistance 
. The ADCY5
rs11708067 and rs9883204 are in close linkage disequilibrium in the Hapmap CEPH (Utah residents with ancestry from northern and western Europe) population data (D' 0.93, r2 0.72, Hapmap data rel 27 - http://hapmap.ncbi.nlm.nih.gov
). rs9883204 is not represented in the Hapmap Indian population (GIH - Gujarathi Indian population), therefore LD cannot be calculated directly within Hapmap. However, a further SNP, rs17361324, which is a proxy for rs9883204 in the CEPH Hapmap data is also a proxy for rs11708067 in the GIH Hapmap data. This may suggest that, the high LD between these two SNPs in the CEPH data is also present in the Indian population and the difference does not appear to be explained by the genetic architecture and will need confirmation in future studies. Additionally, the low birth weight and T2DM risk allele of ADCY5
variant was associated with reduced early insulin response measured by insulinogenic index, consistent with original report by Freathy et al., supportive of a possible role in influencing insulin secretion 
. It is proposed that ADCY5
risk allele may operate by different mechanisms by which they influence birth weight and T2DM risk susceptibility 
, the later probably may be through an effect on insulin secretion rather than insulin resistance. It is worth mentioning that for glucose and insulin, the association detailed in this cohort shows borderline significance and type 2 error cannot be excluded.
The loss of heterozygosity of rs9883204 in our population is probably related to the high endogamy which is commonly seen among Indians. It is generally assumed that an association detected by a well-powered GWAS is in LD with the functional variant. The strong signals in GWAS are related to the functional magnitude of the effect and therefore, we assume this holds good in our population despite a considerable degree of consanguinity.
Although, we have studied, the genetic variants associated with birth weight in one of the largest and homogenous birth cohorts from India, our study has limitations. Our study was adequately powered for CCNL1
, but less strong for ADCY5
to explain the variance observed with these two SNPs. The CV for birth weight in our study was comparable to originally described and this further solidifies our power to detect an association. Also the lower mean birth weight, observed in this population, might potentially be associated with a reduced overall variance in the dependent variable, i.e., reduce the effect of the functional variant on birth weight, which could possibly contribute to the lowered power in our study. Although it is evident that a multiple comparison correction would abolish the modest associations with glycemic traits, we believe that the association is biologically relevant and that loss of statistical significance by multiple testing does not necessarily disprove a true association owing to the homogenous population studied within a small geographical region and the similar allele frequencies reported among Caucasians 
. We did not have the maternal genotype to assess the effect of maternal genetic variants on birth weight due to non-availability of blood sample from the mothers. The low number of diabetes cases in this still young cohort did not allow for observing a possible link between diabetes incidence and birth weight or genetic links between them.
In conclusion, the ‘birth weight-lowering’ variants in ADCY5 and near CCNL1 showing strong associations with birth weight in European cohorts appear to have little or no effect in the Indian setting. However, the ‘birth weight-lowering’ variant in ADCY5 was associated with modest glucose intolerance in early adulthood which reinforces the argument for a genetic link between in utero growth and adult type 2 diabetes.