ADSP and Affiliates Whole Genome Sequencing Report – January 2023

Studies conducted primarily in non-Hispanic White populations have shown that genetic variants that are observed infrequently in populations are important to the development of Alzheimer’s disease (AD). Research has also shown that genetic variation that increases risk or protects against development of AD can be shared across ancestral backgrounds but also may differ based on these categories. Therefore, it is important to study large numbers of individuals from different ancestral backgrounds in order to fully understand and reveal the genetic underpinnings of AD, and to ensure that any prevention or treatment strategies based on genetics work for everyone.

To increase researchers ability to find variants important for AD across and within different populations, the ADSP is whole genome sequencing (WGS) large numbers of participants across the four major ancestral populations of the United States. Foreign studies that include ancestral populations of the United States are also included in the ADSP in order to capture the most genetic variation possible and to allow for important ancestral, social, cultural and environmental questions related to development of AD to be investigated. Here, ancestry/ethnicity population categories (Asian, Black/African American, Hispanic/Latino, and Non-Hispanic White) are based on self-reported or ascribed race or ethnicity as defined by the Office of Management and Budget (OMB) standards and only apply to populations within the United States. Importantly, the genetics field is currently assessing the appropriate use of terminology for population descriptors and genetic variation (see for example Byeon et al., AJHG, 2021 and Kamariza et al., Nat Genet, 2021). To this end, while we follow OMB standards for our population categories, we substitute race with ancestry in our description of population categories. Generally, “race” and “ethnicity” refer to social or cultural categories, and have no biological meaning, whereas “ancestry” refers to a person’s biological ancestors from whom their DNA was genetically inherited. Ancestry can thus also refer to where a majority of a person’s ancestors originated from (i.e. Africa, Asia, Europe) and is often described as “continental ancestry”. Any reference to ancestry is based on the genetically determined ancestry of a population and is designated separately from ethnicity by study investigators. These designations often follow historically defined continental population definitions. ADSP datasets from foreign countries are included ancestry/ethnicity categories which most closely align with their genetically determined ancestry.

To reach the study sample size necessary to detect associations with genetic variants that are not frequently seen in a population ~18,500 cases and ~18,500 controls per ancestry/ethnic population are being included and sequenced as part of the ADSP Follow-Up Study (FUS). The following tables document the progress being made towards this recruitment goal.

Byeon YJJ, Islamaj R, Yeganova L, Wilbur WJ, Lu Z, Brody LC, Bonham VL. Evolving use of ancestry, ethnicity, and race in genetics research – A survey spanning seven decades. AJHG. 108, 12:2215-2223. 2021.

Kamariza M, Crawford L, Jones D, Finucane H. Misuse of the term ‘trans-ethnic’ in genomics research. Nat Genet. 53:1520-1521. 2021.

Presented here are whole genome sequencing (WGS) totals by self-reported race/ethnicity and case/control status for completed and proposed or planned projects in the Alzheimer Disease Sequencing Project (ADSP) Follow-Up Study (FUS). Note that self-reported or ascribed race/ethnicity follow the OMB standards and only apply to US populations. ADSP datasets from foreign countries are included in race/ethnicity categories which most closely align with their genetically determined ancestry . The far right hand columns of the table show the total numbers needed per race/ethnicity to reach the 18,500 case and 18,500 control requirements. The three sections (blue, yellow and orange) represent sequencing which is funded by NIA and is either released (Release 3 and 4) or planned for release in 2023 (Release 5) by the Genome Center for Alzheimer’s Disease (GCAD). These data, once released, are available for use by all qualified researchers with an approved date use plan.

*Following OMB ancestral and ethnic category standards for US populations:
https://orwh.od.nih.gov/toolkit/other-relevant-federal-policies/OMB-standards

This table presents the number of genomes that the ADSP has sequenced as of November 2022 in terms of number of study participants across the four major ancestry groups. To date, the majority of sequencing has been on Non-Hispanic whites. Planned sequencing for the ADSP Follow-Up Study (FUS) 2.0 will continue to reduce this disparity. This is a graphical representation of the GCAD Release 4 block in Sequencing Overview by Case/Control Status and Self-Reported Ancestry/Ethnicity table above. These data are exclusive of the new cohorts that are being brought in by the FUS 2.0 (PAR-21-212).

Presented here are whole genome sequencing (WGS) totals by self-reported race/ethnicity and case/control status for all funded data sets. A subset have been sequenced; a second subset have not been sequenced. Self-reported or ascribed race/ethnicity follow the OMB standards and only apply to US populations. ADSP datasets from foreign countries are included in race/ethnicity categories which most closely align with their genetically determined ancestry. The far-right columns of the table show the total numbers still needed after the sequencing is completed on these subjects in order to reach the 18,500 case and 18,500 control requirements. These are reflected in the bar graph below called, Total Number of ADSP Samples Presently Funded for WGS by Ancestry/Ethnicity.

* Following OMB ancestral and ethnic category standards for US populations:
https://orwh.od.nih.gov/toolkit/other-relevant-federal-policies/OMB-standards