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New Genetic Variants, Trait Associations Uncovered With Chinese Birth Cohort Sequences

NEW YORK – A team from Guangzhou Medical University, the Shenzhen Campus of Sun Yat-sen University, and other centers in China has shared findings from the initial genome sequencing phase of a large birth cohort study centered on the city of Guangzhou and other sites in the southern Chinese province of Guangdong.

"Despite the inherent challenges in establishing and maintaining birth cohorts with long-term follow-up, genomic research using these resources is a critical approach for unravelling the genetic and environmental influences of early life on later-life health," co-senior and co-corresponding authors Xiu Qiu and Huimin Xia from Guangzhou Medical University and the Provincial Clinical Research Center for Child Health and their colleagues wrote in Nature on Wednesday.

Using low-coverage whole-genome sequencing, the researchers assessed 4,053 Chinese individuals for Phase I of the Born in Guangzhou Cohort Study (BIGCS) genome analysis, including members of 332 parent-child trios, more than 1,400 parent-child duos, and 245 unrelated individuals. The researchers collected peripheral blood samples from the adults and cord blood samples from infants for DNA sequencing analysis.

With the resulting sequence collection, the team tracked down more than 56.2 million SNPs or small insertions and deletions, including 18.3 million previously unappreciated variants. Along with an admixed ancestry gradient detected from northern to southern parts of the region, the genetic variant patterns pointed to population structures influenced by individuals' language groups and ethnicity.

"Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS," the authors reported, later noting that the "number of variants per individual exhibited geographical, ethnic, and linguistic patterns."

In a series of genome-wide association studies involving 2,245 adult and 1,808 child participants, meanwhile, the researchers focused on a dozen maternal quantitative traits and six infant traits, uncovering 10 loci linked to eight of the adult traits and three loci associated with two infant traits.

In particular, the team highlighted loci linked to maternal bile acid, gestational weight gain, and lipid-associated traits ranging from infant cord blood low density lipoprotein levels to maternal LDL, total cholesterol, and triglyceride levels. A subset of these associations were then validated using noninvasive prenatal testing data from up to 26,103 pregnancies in China, pointing to the presence of both age-specific and East Asian-specific associations.

Together, the study's authors suggested, their findings "illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures, and early-life experiences in shaping long-term health."

The investigators are continuing to expand the BIGCS cohort, building on their current proof-of-concept analyses. The cohort now includes more than 50,000 deeply phenotyped parent-child trios or maternal-infant pairs, who will be followed over time until the children of pregnant participants reach the age of 18, they said, noting that the study's next sequencing phase is expected to explore genetic contributors to perinatal outcomes.

"As we continue to develop and release genomic data, future efforts will be prioritized to update the variation dataset, reference panel, genotype-phenotype associations, and to quantify the complex interplay of a comprehensive spectrum of environmental and genetic factors during early life and their roles in shaping not only birth outcomes but also childhood and adult health," the authors wrote.

In a related commentary in Nature, University of Bristol integrative epidemiology and population health sciences researcher Nicholas John Timpson said the new BIGCS study "charts another step of the journey towards a large and well-characterized cohort that includes genetic sequencing data."

"The collection and study of such data call for cultural sensitivity and a combination of ethical and scientific rigor, so it is encouraging to see progress in this area," Timpson said, adding that "[w]e should also be excited about having a deeper understanding of populations, sociodemographic histories, and fresh biological insights, as well as about the willingness of BIGCS participants to take part."