Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight

Abstract

To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.

Figure 1

Regional plots of two novel associations with birth weight. For each of the two regions, 3q25 [A] and 3q21 [B], directly genotyped and imputed SNPs are plotted using filled circles with their meta-analysis P values (as −log₁₀ values) as a function of genomic position (NCBI Build 35). In each plot, the discovery stage SNP taken forward to replication stage is represented by a blue diamond (defining a global meta-analysis P value), with its discovery meta-analysis P value denoted by a red diamond. Local LD structure is reflected by the plotted estimated recombination rates (taken from HapMap) in the region around the associated SNPs and their correlated proxies. Each analyzed SNP is represented by circle. The colour scheme of the circles respects LD patterns (HapMap CEU pair-wise r2 correlation coefficients) between top discovery SNP and surrounding variants: white r2<0.2, grey 0.5> r2 >= 0.2, orange 0.8> r2 >= 0.5, red r2 >= 0.8. Gene annotations were taken from the University of California Santa Cruz genome browser.

Figure 1

Regional plots of two novel associations with birth weight. For each of the two regions, 3q25 [A] and 3q21 [B], directly genotyped and imputed SNPs are plotted using filled circles with their meta-analysis P values (as −log₁₀ values) as a function of genomic position (NCBI Build 35). In each plot, the discovery stage SNP taken forward to replication stage is represented by a blue diamond (defining a global meta-analysis P value), with its discovery meta-analysis P value denoted by a red diamond. Local LD structure is reflected by the plotted estimated recombination rates (taken from HapMap) in the region around the associated SNPs and their correlated proxies. Each analyzed SNP is represented by circle. The colour scheme of the circles respects LD patterns (HapMap CEU pair-wise r2 correlation coefficients) between top discovery SNP and surrounding variants: white r2<0.2, grey 0.5> r2 >= 0.2, orange 0.8> r2 >= 0.5, red r2 >= 0.8. Gene annotations were taken from the University of California Santa Cruz genome browser.

Figure 2

Forest plots of the association between birth weight and genotype at each locus. [A] Index SNP rs900400 at 3q25. [B] Index SNP rs9883204 at 3q21. If the index SNP was unavailable, a closely-correlated proxy (HapMap r²>0.9) was used.

Figure 2

Forest plots of the association between birth weight and genotype at each locus. [A] Index SNP rs900400 at 3q25. [B] Index SNP rs9883204 at 3q21. If the index SNP was unavailable, a closely-correlated proxy (HapMap r²>0.9) was used.