ADSP and Affiliates Whole Genome Sequencing Report – October 2023

Introduction

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 racial, ethnic, or ancestral backgrounds but also may differ based on these categories. Therefore, it is important to study large numbers of individuals from different racial, ethnic and 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 racial/ethnic 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. Importantly, “race” and “ethnicity” generally refer to social 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”. Here, racial/ethnic 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 (https://orwh.od.nih.gov/toolkit/other-relevant-federal-policies/OMB-standards) and only apply to populations within the United States. Any reference to ancestry is based on the genetically determined ancestry of a population and is designated separately from race/ethnicity by study investigators. These designations often follow historically defined continental population definitions. ADSP datasets from foreign countries are included in race/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 racial/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.

Sequencing Overview by Case/Control Status and Self-Reported Ancestry/Ethnicity1

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 represent sequencing which is funded by NIA and is either released (Release 3 and 4) or planned for release in 2024 (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.

1Following OMB ancestral and ethnic category standards for US populations:
https://orwh.od.nih.gov/toolkit/other-relevant-federal-policies/OMB-standards

*Numbers include all categories in the Discovery and Discovery Extension (earlier) phases in the project but not FUS 2.0
**Numbers are cumulative

ADSP Samples with WGS Completed by Ancestry/Ethnicity
and Raw Data Released November 2022; QCed Data Released August 2023

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).

FUS 2.0 Datasets
(TOTAL OF ALL FUNDED including samples not yet sequenced by Case/Control Status and Ancestry/Ethnicity1 as of October 2023)

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.

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

* Numbers are cumulative and include the dataset released in Fall of 2022

Total Number of ADSP Samples Presently Funded for WGS by Ancestry/Ethnicity (sequenced and in the queue for sequencing thru 2027)

This table presents the total number of genomes the ADSP presently funded for WGS denoted by study participants across the four major ancestry groups. These data include the first wave of ADSP FUS 2.0 (PAR-21-212) subjects being brought into the study referenced in the FUS 2.0 Datasets table above.

Study Break Out Data for Datasets that are Currently Funded

Self-reported Race/Ethnicity: Black/African American*

Presented here are composite numbers for Black/African American datasets currently funded for WGS under the ADSP FUS (see PAR-17-214, PAR-18-890, and PAR-19-234) and FUS 2.0 (PAR-21-212).

*Applies to US populations only

**Mild Cognitive Impairment/ADRD/Unknown

Self-reported Race/Ethnicity: Asian*

Presented here are composite numbers for Asian datasets currently funded for WGS under the ADSP FUS (see PAR-17-214, PAR-18-890, and PAR-19-234) and FUS 2.0 (PAR-21-212).

*Applies to US populations only

**Mild Cognitive Impairment/ADRD/Unknown

Self-reported Race/Ethnicity: Non-Hispanic White*

Presented here are composite numbers for Non-Hispanic White datasets currently funded for WGS under the ADSP FUS (see PAR-17-214, PAR-18-890, and PAR-19-234) and FUS 2.0 (PAR-21-212).

*Applies to US populations only

**Mild Cognitive Impairment/ADRD/Unknown

Self-reported Race/Ethnicity: Hispanic/Latino and Amerindian*

Presented here are composite numbers for Hispanic/Latino and Amerindian datasets currently funded for WGS under the ADSP FUS (see PAR-17-214, PAR-18-890, and PAR-19-234 and FU:S 2.0 (PAR-21-212).

*Applies to US populations only

**Mild Cognitive Impairment/ADRD/Unknown