Benefits of population genomics
Population genomics turns data into health insights. Increasingly, genotyping data from diverse populations around the globe are complementing the European and Caucasian data that have long dominated biobanks and genetic databases. Researchers worldwide are advancing population genomics studies in focused ethnic or geographic populations to reveal new insights into the interplay between genotype regarding the genetics of disease and lifestyle factors.
Predicting disease risk from genotypes means individuals can make changes to their diet and lifestyle. Improved diagnosis, prognosis, and treatment may also enable better outcomes and help reduce health care costs.
Recent genetic research has revealed that in many common complex diseases, such as some types of heart disease, cancer, diabetes, and brain disorders, multiple common genetic variants of small effect may play a greater role than rare single-gene mutations. A single trait may be affected by thousands of variants throughout the genome. While one variant among thousands might not be useful in predicting complex traits, quantifying the cumulative effects of large sets of variants into a single metric, the polygenic risk score (PRS), may overcome this challenge.
Polygenic risk score (PRS)
A PRS is calculated from genome-wide association studies (GWASs) by totaling an individual’s risk-associated alleles and weighting them by the magnitude of their effect. Leading genetic studies and biobanks are integrating population variation, imputation analysis, epidemiology, and biological function into large-scale, state-of-the-art association studies to understand how the complex interactions between genes, environment, and lifestyle relate to health.
At a recent Thermo Fisher Scientific-sponsored talk, Sir Peter Donnelly, founder and CEO of Genomics PLP, said, “By studying these data and ongoing medical information from participants, researchers can evaluate the risks posed by relevant gene variants—and discover new ones.” But Donnelly also stressed that to be useful, findings depend on the accuracy and completeness of the data used to calculate them.
Biobanks provide power in numbers
Predictive genomics holds tremendous promise. A dataset that can properly inform medical providers about a person’s disease risks and pharmacological possibilities must contain genomic data on enough people to achieve statistical relevance. This is the premise of a biobank.
The world’s leading genetic studies and biobanks are integrating knowledge of population variation, imputation analysis, epidemiology, and biological function into the design of large-scale, state-of-the-art association studies to understand how the complex interactions between genes, environment, and lifestyle relate to health. The genetic information held in large biobanks makes rich data sets of billions of genotypes available to scientists for a wide range of research applications. Each biobank has its own application focus, genotyping strategy, and sources of samples and data from volunteer contributors.
For example, UK Biobank has compiled genotypes of 500,000 consenting individuals from within the UK National Health Service (UK NHS), along with blood and urine samples and complete medical records for each participant. UK Biobank is an exceptionally valuable resource because the UK NHS treats the single largest group of people anywhere in the world and keeps detailed records on each subject from birth to death. The subjects’ medical records are accessible across the entire system, and the data are available to any researcher interested in the wide range of diseases and traits covered by UK Biobank.
Other biobanks are also rich resources for investigating causes of diseases in specific populations and worldwide. The number of countries and organizations that are beginning to build their own biobanks is growing. For example:
- The FinnGen project launched in October 2018. It is drawing together genetic data and digital health records from a wide network of biobanks across Finland to enable medical innovations such as better diagnostics and new therapies.
- The Tohoku University Tohoku Medical Megabank (TMM) is also based on a unique and specific population. This project is using genetic and biospecimen data from individuals in the Tohoku region of Japan to understand health consequences following the devastating 2011 earthquake, and also to develop a new advanced medical system for the region.
- The China Kadoorie Biobank (CKB) is leveraging China’s very large population to investigate the main genetic and environmental causes of common chronic diseases in the Chinese population. The biobank contains genetic data, phenotypic measurements, and blood samples for more than 510,000 adults across 10 geographic regions in China.
- The U.S. Veterans Affairs Office is focusing on U.S. military veterans. They initiated the Million Veteran Program (MVP), which is building a database of genetic data and health information to study military-related and other diseases.
Population genomics microarray analysis
Scientists from many of the world’s largest population genetic epidemiology projects have chosen Thermo Fisher Scientific to tailor the array design for their studies. Thermo Fisher’s novel modular content approach makes designing custom arrays fast and simple. Axiom array content modules exist within the Axiom Genomic Database, which covers 26 million SNPs and indels. (Single nucleotide polymorphism, or SNP, changes a single nucleotide in the DNA sequences, whereas an indel incorporates or removes one or more nucleotides.) Modules can be combined into an array design and easily modified by adding, removing, and replacing markers to help meet the needs of your study.
The ability to choose a predesigned array, customize an existing design, or create an entirely new array for GWAS, replication, or fine-mapping studies has made the Axiom Biobank Genotyping Solution the platform of choice for large-scale genotyping studies. As innovative PRS calculations play an increasing role in disease treatment and prevention, Thermo Fisher will help ensure your study has the most complete and accurate data available
Predictive genomics workflow
Population genotyping projects are enabling precision medicine decisions and helping lead to the future of improved health outcomes. Many national governments and large organizations are investing in scaling up genotyping infrastructure to ensure personalized solutions.
The Axiom Solution consists of a technology platform that includes assay biochemistry, automated and manual target preparation options, multiple array plate formats, and array processing on the GeneTitan Multi-Channel (MC) Instrument. This solution has applications in human genetics and microbiome research.
The Axiom assay and workflow begins with purified genomic DNA. The first part of the assay and workflow is Target Preparation, which includes whole genome amplification on day one, followed by DNA fragmentation and overnight precipitation on day two. On day three the DNA is resuspended and prepared for hybridization on the array. Finally, washing, ligation, and staining occurs on the GeneTitan instrument followed by scanning of the plate. Target preparation aims to prepare the genomic targets of interest so that they can be successfully attached, or “hybridized” to the synthesized probes on the microarray for accurate results. Following hybridization, array processing involves washing non-specific binding DNA and scanning the microarray plate to detect the fluorescence signal from the genomic targets of interest. Finally, genotypes are reported in Axiom Analysis Suite.
The ability to choose a predesigned array, customize an existing design, or create an entirely new array for GWAS, replication, or fine-mapping studies has made the Axiom Biobank Genotyping Solution the platform of choice for large-scale genotyping studies. As innovative PRS calculations play an increasing role in disease treatment and prevention, Thermo Fisher will ensure your study has the most complete and accurate data available
Let’s dive deeper into each step:
- Whole genome amplification: Since starting genomic DNA is limited and/or finite and typically original crude samples from which the DNA was extracted are also finite or not available, it is important to amplify the limited amount of starting genomic DNA so that there is plenty of DNA available to hybridize to the synthesized complimentary probes on the array plate. The Axiom assay requires 200 ng of total genomic DNA for whole genome amplification. This takes about 24 hours in a 37°C oven.
- Fragmentation: Cut the DNA into fragment sizes that are optimal for array hybridization. If the DNA is too long, it may not bind. The Axiom assay utilizes enzymes that randomly cut DNA into 25 to 125 base pair (bp) fragments.
- Precipitation: Purify and collect all the DNA fragments. Overnight precipitation is standard, but there is an option for a three-hour precipitation for a quicker turnaround time.
- Hybridization: DNA fragments pair to complimentary probe sequences on the array.
- Wash, ligate, stain: The bound target is washed under stringent conditions to remove non-specific background to minimize background noise caused by random ligation events. Each polymorphic nucleotide is queried via a multi-color ligation event carried out on the array surface. After ligation, the arrays are stained and imaged on the Gene Titan MC Instrument.
- Scan: Detection of fluorescent signal
- Data Analysis: Primary and secondary analysis. Primary analysis is generation of the genotypes. Secondary analysis includes any analysis of the genotypes to understand groups of samples, genes, variants, etc.
Propel workflow
The above steps (excluding data analysis) have been optimized into a shortened two-day workflow, the Axiom Propel workflow, with completion of scanning of the arrays by the end of day 2. In addition, the Axiom Propel workflow has been optimized to include benchtop automation to increase the throughput, allowing the processing of more plates in two days than the standard manual Axiom 2.0 assay.
For Research Use Only. Not for use in diagnostic procedures.