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Birth Weight-Associated Loci Also Linked to Later Risk of Adult-Onset Diseases

NEW YORK (GenomeWeb) – An international team of researchers has uncovered some 60 genomic loci that are associated with birth weight, and further found that these genomic regions are linked to people's likelihood of developing metabolic disease later in life.

The team conducted a genome-wide association study meta-analysis that drew on nearly 154,000 people from a range of ethnicities and uncovered 60 loci where the fetal genotype was associated with birth weight. As observational studies have suggested that birth weight is linked to the later development of conditions like type 2 diabetes and cardiovascular disease, the researchers examined whether there were genetic associations between birth weight and certain health indices like BMI and systolic blood pressure. As they reported today in Nature, they uncovered an inverse genetic correlation between birth weight and type 2 diabetes and coronary artery disease.

"This study has revealed how the small genetic differences between individuals can collectively have quite large effects on birth weight, and how those same genetic differences are often linked to poor health in later life," joint senior author Rachel Freathy from the University of Exeter Medical School said in a statement.

She and her colleagues combined GWAS data for birth weight on 153,781 people from 37 studies, including people of European, African American, Chinese, Moroccan, and other ethnicities. After adjusting for gestational age where possible and imputing genotypes within the 1000 Genomes Project and UK10K datasets, the researchers uncovered 60 loci associated with birth weight at genome-wide significance.

Of these loci, 59 were autosomal, 53 were novel, and many of their lead variants mapped to non-coding sites, the researchers noted. They further estimated that the genome-wide signals emanating from the autosomal loci explained about 2 percent of the variance in birth weight.

Maternal genes, Freathy and her colleagues added, could also affect infant birth weight, but based on a series of analyses, they said fetal genotype appeared to be the predominant driver of birth weight.

Using a linkage disequilibrium score regression, the investigators examined the genetic correlation between birth weight and certain health-linked traits. While birth weight showed positive genetic correlations with anthropometric and obesity-related traits like waist circumferences and BMI in European ancestry samples, it exhibited inverse genetic correlations with coronary artery disease, systolic blood pressure, and type 2 diabetes.

Through gene set enrichment analyses, the researchers noted that the loci they uncovered were enriched in a dozen pathways, especially ones involved in metabolism, growth, and development. A protein-protein interaction analysis likewise uncovered PPI networks enriched for birth weight-association scores were themselves enriched for metabolism, growth, and development processes.

The researchers also tested whether loci previously linked to type 2 diabetes were associated with birth weight. Some diabetes risk alleles were associated with lower birth weight, though others were linked to higher birth weight. These conflicting associations are likely due to differential effects of fetal and maternal genotypes, Freathy and her colleagues said.

Paternal diabetes has been linked with lower birth weight, which the researchers said suggests that the diabetes risk alleles reduce growth and is in line with the fetal insulin hypothesis that says reduced insulin secretion or signaling can lead to reduced fetal growth and, years later, diabetes risk. Maternal diabetes, meanwhile, is linked to increased birth weight, possibly as maternal hyperglycemia stimulates fetal insulin secretion.

“These findings provide vital clues to some of the processes that act over decades of life to influence an individual’s chances of developing diabetes and heart disease," co-lead author Mark McCarthy from the University of Oxford said in a statement. "These should highlight new approaches to treatment and prevention."