Evidence of recent and ongoing admixture in the U.S. and influences on health and disparities.

Many researchers in genetics and social science incorporate information about race in their work. However, migrations (historical and forced) and social mobility have brought formerly separated populations of humans together, creating younger generations of individuals who have more complex and diverse ancestry and race profiles than older age groups. Here, we sought to better understand how temporal changes in genetic admixture influence levels of heterozygosity and impact health outcomes. We evaluated variation in genetic ancestry over 100 birth years in a cohort of 35,842 individuals with electronic health record (EHR) information in the Southeastern United States. Using the software STRUCTURE, we analyzed 2,678 ancestrally informative markers relative to three ancestral clusters (African, East Asian, and European) and observed rising levels of admixture for all clinically-defined race groups since 1990. Most race groups also exhibited increases in heterozygosity and long-range linkage disequilibrium over time, further supporting the finding of increasing admixture in young individuals in our cohort. These data are consistent with United States Census information from broader geographic areas and highlight the changing demography of the population. This increased diversity challenges classic approaches to studies of genotype-phenotype relationships which motivated us to explore the relationship between heterozygosity and disease diagnosis. Using a phenome-wide association study approach, we explored the relationship between admixture and disease risk and found that increased admixture resulted in protective associations with female reproductive disorders and increased risk for diseases with links to autoimmune dysfunction. These data suggest that tendencies in the United States population are increasing ancestral complexity over time. Further, these observations imply that, because both prevalence and severity of many diseases vary by race groups, complexity of ancestral origins influences health and disparities.

Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.

PURPOSE: The early-onset colorectal cancer (EOCRC) burden differs across racial/ethnic groups, yet the role of germline genetic predisposition in EOCRC disparities remains uncharacterized. We defined the prevalence and spectrum of inherited colorectal cancer (CRC) susceptibility gene variations among patients with EOCRC by race and ethnicity. PATIENTS AND METHODS: We included individuals diagnosed with a first primary CRC between age 15 and 49 years who identified as Ashkenazi Jewish, Asian, Black, Hispanic, or White and underwent germline genetic testing of 14 CRC susceptibility genes performed by a clinical testing laboratory. Variant comparisons by racial and ethnic groups were evaluated using chi-square tests and multivariable logistic regression adjusted for sex, age, CRC site, and number of primary colorectal tumors. RESULTS: Among 3,980 patients with EOCRC, a total of 530 germline pathogenic or likely pathogenic variants were identified in 485 individuals (12.2%). By race/ethnicity, 12.7% of Ashkenazim patients, 9.5% of Asian patients, 10.3% of Black patients, 14.0% of Hispanic patients, and 12.4% of White patients carried a germline variant. The prevalence of Lynch syndrome (P = .037), as well as APC, CHEK2, MLH1, monoallelic MUTYH, and PTEN variants, varied by race/ethnicity among patients with EOCRC (all P < .026). Ashkenazim and Hispanic patients had significantly higher odds of presenting with a pathogenic APC variant, which included p.I1307K (odds ratio [OR], 2.67; 95% CI, 1.30 to 5.49; P = .007) and MLH1 variant (OR, 8.69; 95% CI, 2.68 to 28.20; P = .0003), respectively, versus White patients in adjusted models. CONCLUSION: Germline genetic features differed by race/ethnicity in young patients with CRC, suggesting that current multigene panel tests may not be representative of EOCRC risk in diverse populations. Further study is needed to optimize genes selected for genetic testing in EOCRC via ancestry-specific gene and variant discovery to yield equitable clinical benefits for all patients and to mitigate inequities in disease burden.

Racial/Ethnic and Sex Differences in Somatic Cancer Gene Mutations among Patients with Early-Onset Colorectal Cancer.

Molecular features underlying colorectal cancer disparities remain uncharacterized. Here, we investigated somatic mutation patterns by race/ethnicity and sex among 5,856 non-Hispanic white (NHW), 535 non-Hispanic Black (NHB), and 512 Asian/Pacific Islander (API) patients with colorectal cancer (2,016 early-onset colorectal cancer patients: sequencing age <50 years). NHB patients with early-onset nonhypermutated colorectal cancer, but not API patients, had higher adjusted tumor mutation rates than NHW patients. There were significant differences for LRP1B, FLT4, FBXW7, RNF43, ATRX, APC, and PIK3CA mutation frequencies in early-onset nonhypermutated colorectal cancers between racial/ethnic groups. Heterogeneities by race/ethnicity were observed for the effect of APC, FLT4, and FAT1 between early-onset and late-onset nonhypermutated colorectal cancer. By sex, heterogeneity was observed for the effect of EP300, BRAF, WRN, KRAS, AXIN2, and SMAD2. Males and females with nonhypermutated colorectal cancer had different trends in EP300 mutations by age group. These findings define genomic patterns of early-onset nonhypermutated colorectal cancer by race/ethnicity and sex, which yields novel biological clues into early-onset colorectal cancer disparities. SIGNIFICANCE: NHBs, but not APIs, with early-onset nonhypermutated colorectal cancer had higher adjusted tumor mutation rates versus NHWs. Differences for FLT4, FBXW7, RNF43, LRP1B, APC, PIK3CA, and ATRX mutation rates between racial/ethnic groups and EP300, KRAS, AXIN2, WRN, BRAF, and LRP1B mutation rates by sex were observed in tumors of young patients. See related commentary by Shen et al., p. 530 . This article is highlighted in the In This Issue feature, p. 517.