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Illumina, Collaborators Design Multi-Ethnic Genotyping Array to Empower GWAS in Diverse Populations

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NEW YORK (GenomeWeb) – Illumina and collaborators from several consortia have developed a new genotyping microarray optimized for genome-wide association studies in populations of diverse ancestries and backgrounds.

Dubbed the Infinium Multi-Ethnic Genotyping Array, or MEGA, the San Diego vendor is offering the 1.7-million marker chip through the end of the month with an introductory price of $74 per sample, said Peter Fromen, senior director of product marketing for the company's life sciences business.

Fromen noted that while there has been a significant investment in detecting common genetic variants associated with complex disease in European populations, there are advantages to studies focused on diverse human populations, an opportunity that the MEGA chip addresses.

"This array is meant to empower the research community," Fromen told GenomeWeb. "It offers more rare variants suitable for association studies across ethnicities," he said. "This is another example of how we through deep collaboration with customers and consortiums have tried to bring out the best content to fuel research and to make it available to the general market."

The two groups most involved with the creation of the new MEGA array are the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA), and the Population Architecture using Genomics and Epidemiology (PAGE) consortiums.

Funded by the US National Institutes of Health's National Heart, Lung and Blood Institute, CAAPA aims to identify genes that confer risk to asthma among individuals of African ancestry, as well as to catalog genetic diversity in populations of African descent, especially those whose ancestry reflects the African diaspora in the Americas. The consortium CAAPA involves investigators representing 10 national and five international academic institutions.

PAGE is supported through the US NIH National Human Genome Research Institute. The consortium’s research is focused on explaining the differences in health disparities in different populations by studying the nuances of the underlying genetic causes in those populations. PAGE has catalogued genetic diversity in several US populations, including African Americans, Hispanics, Pacific Islanders, and East Asians, with a particular focus on populations with mixed ancestry and backgrounds.

Kathleen Barnes, a professor of medicine at Johns Hopkins University and member of CAPPA, said the consortium decided to develop a new chip for future association studies because most of the whole-genome genotyping arrays on the market are focused on European populations.

"We were frustrated with the tools that existed for GWAS," Barnes told GenomeWeb. "The commercially available chips were not made for finding associations in African Americans."

To develop content for the array, CAAPA together with Illumina sequenced the genomes of 692 individuals with African ancestry from 21 sites in the Americas, including eight sites in the US, three in the Caribbean, nine in Latin and South America, and one in Africa.

"African Americans suffer disproportionately from asthma, which has led us to speculate that there may be a genetic basis that is unique to African Americans," said Barnes. "We aimed to design a new SNP chip that filled in the blanks of the commercial chips."

As both PAGE and CAAPA study populations of mixed ancestry such as African Americans or Latinos, the full design of the GWAS scaffold also required leveraging whole/genome data from more diverse populations. The PAGE group selected additional sites for the array from the 2,504 sequenced individuals, representing 26 global populations, from the 1000 Genomes Project. The SNPs were designed to improve performance for imputation across diverse populations.

According to Fromen, this content, together with genome wide tag SNPs and multiethnic exome content designed by PAGE from more than 36,000 individuals in diverse ethnic groups, was used to inform the design of the MEGA chip. Illumina and its collaborators used the Infinium HumanCore BeadChip as the basis for the array design, he said, meaning that the array is backward compatible with data from samples genotyped using the HumanCore.

The new chip also includes exonic content of over 400,000 markers; more than 17,000 variants relevant to clinical and pharmacogenetic studies; an additional 23,000 hand-curated variants selected for functional, immunological, oncological, ancestry, forensic, and common and rare disease applications; and the capacity to add up to 300,000 custom markers.

Chip design was completed in October 2014, and the array is available in an eight-sample format, meaning that researchers can run eight samples on each chip.

"This is for the world to use  researchers, pharmas, biobanks," said John Picuri, a product manager for Illumina. Picuri told GenomeWeb that Illumina has already received interest in the new chip "from every kind of customer around the world."

In a statement provided to GenomeWeb, Illumina elaborated that studies using the MEGA chip should "shed light on genetic associations with common and rare traits and provide insight to epidemiologists, healthcare practitioners, population geneticists, and genomic researchers interested in findings across diverse populations."

The company noted that its partners developed new tagging strategies to create an array with the power to perform association studies in diverse populations.

CAAPA's Barnes said that the consortium has already completed the genotyping of 10,000 African American and African Caribbean asthmatics and hopes to have some preliminary results available in the next two to three months. And many more are in the pipeline. Barnes said that CAAPA has about 8,000 additional samples available for genotyping on the MEGA chip.

"We think we are going to get a lot of mileage out of this array," said Barnes. "It contains double the variation of the Africans [sequenced] from the 1000 Genomes Project," she said.

Looking ahead, CAAPA is also collaborating with the Human Heredity and Health in Africa (H3Africa) initiative to obtain more information about continental African populations. H3Africa is supported by the NIH, the UK's Wellcome Trust, and the African Society of Human Genetics to study genetic diversity in health and disease in African populations.

Eimear Kenny, an assistant professor of genetics and genomic science at the Icahn School of Medicine at Mount Sinai in New York and member of the PAGE consortium, told GenomeWeb that PAGE intends to genotype 50,000 samples in the next few months on the MEGA chip, including samples from 22,000 Hispanics, 15,000 African Americans, and smaller cohorts of East Asians and Pacific Islanders.

"MEGA provides the advantage of having a single multiplex platform that supports multiethnic variant discovery," Kenny said. "We are looking at disease loci in diverse populations to review local linkage disequilibrium structure, and to better enable discovery of disease variants across these populations," she added.

CAAPA and PAGE also intend to share data in the future. For instance, PAGE could use CAAPA's genotyped African-American samples as a control population in future association studies, Kenny said. And other groups that use the array will also be able to pool their data with CAAPA and PAGE.

"We believe the data will grow over time and grow in terms of diversity," said Kenny. "We are contacted every day by groups that are interested in using the chip."

Illumina has renewed its focus on the array market in recent years. At the recent JP Morgan Healthcare Conference held earlier this month in San Francisco, CEO Jay Flatley told investors that the firm intends to continue to invest in its array business.

"The investment is spread across a number of areas in the array business," Fromen said. "We are making sure we have the most relevant, up-to-date content and the MEGA array is absolutely part of this investment."

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