Exome sequencing of 628,388 individuals identifies common and rare variant associations with clonal hematopoiesis phenotypes

Clonal hematopoiesis (CH) refers to the expansion of certain blood cell lineages and has been associated with aging and adverse health outcomes. Here, we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal hematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 27 loci (24 novel) where germline genetic variation influences CH/CHIP predisposition, including missense variants in the DNA-repair gene PARP1 and the lymphocytic antigen coding gene LY75 that are associated with reduced incidence of CH/CHIP. Analysis of 5,194 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID outcomes, cardiovascular disease, hematologic traits, malignancy, smoking, obesity, infection, and all-cause mortality. Longitudinal analyses revealed that one of the CHIP subtypes, DNMT3A-CHIP, is associated with the subsequent development of myeloid but not lymphoid leukemias, and with solid cancers including prostate and lung. Additionally, contrary to previous findings from the initial 50,000 UKB exomes, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogenous phenotypes with shared and unique germline genetic causes and varied clinical implications.

Poking COVID-19: Insights on Genomic Constraints among Immune-Related Genes between Qatari and Italian Populations

Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, leading to better targeting of care and vaccination. Italy was the epicentre for the spread of COVID-19 in Europe, the first country to go into a national lockdown and has one of the highest COVID-19 associated mortality rates. Qatar, on the other hand has a very low mortality rate. In this study, we compared whole-genome sequencing data of 14398 adults and Qatari-national to 925 Italian individuals. We also included in the comparison whole-exome sequence data from 189 Italian laboratory-confirmed COVID-19 cases. We focused our study on a curated list of 3619 candidate genes involved in innate immunity and host-pathogen interaction. Two population-gene metric scores, the Delta Singleton-Cohort variant score (DSC) and Sum Singleton-Cohort variant score (SSC), were applied to estimate the presence of selective constraints in the Qatari population and in the Italian cohorts. Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction.

Poking COVID-19: insights on genomic constraints among immune-related genes between Qatari and Italian populations

Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, leading to better targeting of care and vaccination. Italy was the epicentre for the spread of COVID-19 in Europe, the first country to go into a national lockdown and has one of the highest COVID-19 associated mortality rates. Qatar, on the other hand has a very low mortality rate. In this study, we compared whole-genome sequencing data of 14398 adults and Qatari-national to 925 Italian individuals. We also included in the comparison whole-exome sequence data from 189 Italian laboratory confirmed COVID-19 cases. We focused our study on a curated list of 3619 candidate genes involved in innate immunity and host-pathogen interaction. Two population-gene metric scores, the Delta Singleton-Cohort variant score (DSC) and Sum Singleton-Cohort variant score (SSC), were applied to estimate the presence of selective constraints in the Qatari population and in the Italian cohorts. Results based on DSC SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction.

Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration

<p>Objective: Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multi-ethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes.</p> <p> </p> <p>Research design and methods: We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines.</p> <p> </p> <p>Results: 93 of 3,333 participants (2.8%) carried an LP/P variant in <i>HNF4A </i>(16 participants)<i>, GCK </i>(23)<i>, HNF1A </i>(44), <i>PDX1</i> (5), <i>INS</i> (4), and <i>CEL</i> (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 <i>vs</i> 13.6 ± 2.3 years, <i>P</i>=0.002) and lower fasting C-peptide levels (3.0 ± 1.7 <i>vs</i> 4.7 ± 3.5 ng/mL, <i>P</i><0.0001). Youth with MODY were less likely to have hypertension (6.9% <i>vs</i> 19.5%, <i>P</i>=0.007) and had higher HDL cholesterol (43.8 <i>vs</i> 39.7 mg/dL, <i>P=</i>0.006). </p> <p> </p> Conclusions: By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n=83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria to select individuals for genetic testing.

Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration

<p>Objective: Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multi-ethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes.</p> <p> </p> <p>Research design and methods: We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines.</p> <p> </p> <p>Results: 93 of 3,333 participants (2.8%) carried an LP/P variant in <i>HNF4A </i>(16 participants)<i>, GCK </i>(23)<i>, HNF1A </i>(44), <i>PDX1</i> (5), <i>INS</i> (4), and <i>CEL</i> (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 <i>vs</i> 13.6 ± 2.3 years, <i>P</i>=0.002) and lower fasting C-peptide levels (3.0 ± 1.7 <i>vs</i> 4.7 ± 3.5 ng/mL, <i>P</i><0.0001). Youth with MODY were less likely to have hypertension (6.9% <i>vs</i> 19.5%, <i>P</i>=0.007) and had higher HDL cholesterol (43.8 <i>vs</i> 39.7 mg/dL, <i>P=</i>0.006). </p> <p> </p> Conclusions: By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n=83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria to select individuals for genetic testing.

Variants in ACE2 and TMPRSS2 Genes Are Not Major Determinants of COVID-19 Severity in UK Biobank Subjects

It is plausible that variants in the ACE2 and TMPRSS2 genes might contribute to variation in COVID-19 severity and that these could explain why some people become very unwell whereas most do not. Exome sequence data was obtained for 49,953 UK Biobank subjects, of whom 82 had tested positive for SARS-CoV-2 and could be presumed to have severe disease. A weighted burden analysis was carried out using SCOREASSOC to determine whether there were differences between these cases and the other sequenced subjects in the overall burden of rare, damaging variants in ACE2 or TMPRSS2. There were no statistically significant differences in weighted burden scores between cases and controls for either gene. There were no individual DNA sequence variants with a markedly different frequency between cases and controls. Whether there are small effects on severity, or whether there might be rare variants with major effect sizes, would require studies in much larger samples. Genetic variants affecting the structure and function of the ACE2 and TMPRSS2 proteins are not the main explanation for why some people develop severe symptoms in response to infection with SARS-CoV-2. This research was conducted using the UK Biobank Resource.

Investigation of association of rare, functional genetic variants with heavy drinking and problem drinking in exome sequenced UK Biobank participants

AimsThe study aimed to identify specific genes and functional genetic variants affecting susceptibility to two alcohol related phenotypes: heavy drinking and problem drinking.MethodsPhenotypic and exome sequence data was downloaded from the UK Biobank. Reported drinks in the last 24 hours was used to define heavy drinking while responses to a mental health questionnaire defined problem drinking. Gene-wise weighted burden analysis was applied, with genetic variants which were rarer and/or had a more severe functional effect being weighted more highly. Additionally, previously reported variants of interest were analysed inidividually.ResultsOf exome sequenced subjects, for heavy drinking there were 8,166 cases and 84,461 controls while for problem drinking there were 7,811 cases and 59,606 controls. No gene was formally significant after correction for multiple testing but three genes possibly related to autism were significant at p < 0.001, FOXP1, ARHGAP33 and CDH9, along with VGF which may also be of psychiatric interest. Well established associations with rs1229984 in ADH1B and rs671 in ALDH2 were confirmed but previously reported variants in ALDH1B1 and GRM3 were not associated with either phenotype.ConclusionsThis large study fails to conclusively implicate any novel genes or variants. It is possible that more definitive results will be obtained when sequence data for the remaining UK Biobank participants becomes available and/or if data can be obtained for a more extreme phenotype such as alcohol dependence disorder. This research has been conducted using the UK Biobank Resource.Short summaryTests for association of rare, functional genetic variants with heavy drinking and problem drinking confirm the known effects of variants in ADH1B and ALDH2 but fail to implicate novel variants or genes. Results for three genes potentially related to autism suggest they might exert a protective effect.

Abstract 13585: Genomics-first Evaluation of Phenotypes Associated With Pathogenic or Likely Pathogenic Transthyretin Variants

Introduction: Hereditary transthyretin ( TTR ) amyloidosis as a cause of cardiomyopathy has historically been challenging to diagnose. With increased genetic testing, quantification of penetrance and disease associations through genomics-first approach provides a first step towards improved diagnosis and treatment. Methods: In the Geisinger MyCode Community Health Initiative, we identified pathogenic and likely pathogenic (P/LP) variants in TTR from 135,878 individuals with exome sequence data linked to electronic health records (DiscovEHR cohort) using ANNOVAR. We compared diagnoses and imaging findings between TTR variant carriers/noncarriers using SAIGE mixed linear models. Results: We observed 7 P/LP TTR variants (6 P, 1 LP) in 158 individuals (0.12%; 142 P, 16 LP). Median carrier age was 52 (IQR: 37-61) and 43% were male. The most common variant was V122I (i.e., p.V142I; 114, 0.08%). Most TTR variant carriers were of African ancestry (58%), all of whom carried V122I, consistent with the frequency of this variant in that population (2.6%). Observed associations with cardiac amyloidosis (odds ratio (OR): 2.8E 20 , p = 0.03) and non-specific amyloidosis (OR: 4E 4 , p = 0.03) were significant, although prevalence was low (n = 1 and 2 TTR carriers, respectively). No associations were observed with other specified diagnoses (Figure) or imaging findings. Considering only individuals aged ≥60, we observed a significant association with non-ischemic, non-dilated cardiomyopathy diagnoses (OR: 5.8, p=0.04) involving carriers of V122I (n = 3), V30M (p.V50M), T60A (p.T80A), and I68L (p.I88L; n = 1 each). Conclusion: Genomics-first screening of a clinical population for P/LP variants in TTR has a moderate to high yield depending on population ancestry. In the absence of symptoms or family history, initiating routine surveillance may be most appropriate after age 60. Deeper phenotyping is warranted to better characterize penetrance and ramifications for management.