Caucasian Ancestry Research Articles

Genetic risk of Alzheimer’s disease is linked to short sleep duration

AbstractBackgroundSleep disturbances including short sleep duration are common in older adults, especially in those with Alzheimer’s disease (AD). However, it is unclear to what extent sleep duration is a manifestation of AD disease process. We examined whether genetic variants related to AD influence sleep duration in middle‐aged and older adults using a Mendelian randomization (MR) approach.MethodWe examined 406,687 UK Biobank participants without dementia at enrollment, with Caucasian genetic ancestry, and who self‐reported sleep duration at baseline (2006‐2010). Sleep duration was assessed by asking: “About how many hours sleep do you get in every 24 hours? (please include naps).” A genetic risk score for AD (AD‐GRS) was calculated as a weighted sum of 23 previously identified AD‐related single nucleotide polymorphisms in individuals of European ancestry. AD diagnosis was assessed over follow‐up (to 2018) based on ICD‐9/10 codes. We evaluated whether genetic risk for AD influenced sleep duration using two steps: first we used linear regression to examine the association between AD‐GRS and sleep duration, adjusting for age, sex and principle components for genetic ancestry. Next, we conducted a two‐stage least square regression using AD‐GRS as an instrumental variable for AD diagnosis to estimate the magnitude of the effect of AD on sleep duration. We also stratified the analysis by age at baseline (≤55y or >55y).ResultParticipants (aged 56.91±8.00y) had an average sleep duration of 7.2 (Standard deviation [SD]=1.1) hours and AD‐GRS of 0.11 (SD=0.40; range:‐1.15∼1.85). Higher AD‐GRS score predicted shorter sleep duration (b= ‐0.013, 95%CI:‐0.022,‐0.005), mainly among those aged over 55y (b= ‐0.023, 95%CI:‐0.034,‐0.012) and not in those 55y or younger (b= 0.006, 95%CI:‐0.012,0.013); p for interaction by age=0.02. Analysis using AD‐GRS as an instrumental variable for AD diagnosis suggested that participants with AD diagnosis had 1.76 hrs (b=‐1.76, 95%CI: ‐2.62, ‐0.90) shorter sleep duration in those aged >55y.ConclusionUsing a novel analytical approach, we found that higher genetic risk for AD predicted shorter sleep duration among older adults. This suggests shared genetic pathways; the biologic processes that lead to AD may also affect sleep duration.

Human genetic determinants of the gut microbiome and their associations with health and disease: a phenome-wide association study

Abstract Background Recent small-scale studies have suggested a link between the human gut microbiome and highly prevalent diseases. However, the extent to which the human gut microbiome can be considered a determinant of disease and healthy aging has not been well established. In this study, we aimed to determine the spectrum of diseases that are linked to the human gut microbiome through the utilization of its genetic determinants as a proxy for its composition. Methods Data from 422,417 unrelated individuals of Caucasian British ancestry with available genotype and matching genetic data from the UK biobank was analysed in this study. 35 single nucleotide polymorphisms (SNPs) known to influence the human gut microbiome were used to perform the phenome-wide association study. Our main outcome was the probability (risk) of health and disease outcomes associated with human genetic determinants of the microbiome. Results From the total sample analysed (mean age was 57±8 years), 194,567 (46%) subjects were male. Median exposure was 66-person years (interquartile range 59 to 72). Seven SNPs known to influence the human gut microbiome were significantly associated with 29 health and disease outcomes (false discovery rate <5%, P value <9.14×10–4) including food intake, health status parameters (inflammation, blood pressure and lipid levels), hypertension, type 2 diabetes mellitus, hypercholesterolemia, heart failure, renal failure, and osteoarthritis. Conclusions Human genetic determinants of the gut microbiome are associated with 29 specific health and disease outcomes including hypertension, type 2 diabetes mellitus, hypercholesterolemia, heart failure, renal failure, and osteoarthritis. Microbiota and their metabolites play an important role in the interplay between overlapping pathophysiological processes and could be considered as potential targets for the maintenance of health and reduction of disease risk. Heat map Funding Acknowledgement Type of funding source: None

Iris Colour and the Risk of Developing Uveal Melanoma.

Uveal melanoma (UM) is a global disease which especially occurs in elderly people. Its incidence varies widely between populations, with the highest incidence among Caucasians, and a South-to-North increase in Europe. As northern Europeans often have blond hair and light eyes, we wondered whether iris colour may be a predisposing factor for UM and if so, why. We compared the distribution of iris colour between Dutch UM patients and healthy Dutch controls, using data from the Rotterdam Study (RS), and reviewed the literature regarding iris colour. We describe molecular mechanisms that might explain the observed associations. When comparing a group of Dutch UM patients with controls, we observed that individuals from Caucasian ancestry with a green/hazel iris colour (Odds Ratio (OR) = 3.64, 95% Confidence Interval (CI) 2.57–5.14) and individuals with a blue/grey iris colour (OR = 1.38, 95% CI 1.04–1.82) had a significantly higher crude risk of UM than those with brown eyes. According to the literature, this may be due to a difference in the function of pheomelanin (associated with a light iris colour) and eumelanin (associated with a brown iris colour). The combination of light-induced stress and aging may affect pheomelanin-carrying melanocytes in a different way than eumelanin-carrying melanocytes, increasing the risk of developing a malignancy.

Association of genetic risk for Alzheimer disease and hearing impairment.

To test the hypothesis that incipient Alzheimer disease (AD) may adversely affect hearing and that hearing loss may adversely affect cognition, we evaluated whether genetic variants that increase AD risk also increase problem hearing and genetic variants that increase hearing impairment risk do not influence cognition. UK Biobank participants without dementia ≥56 years of age with Caucasian genetic ancestry completed a Digit Triplets Test of speech-in-noise hearing (n = 80,074), self-reported problem hearing and hearing with background noise (n = 244,915), and completed brief cognitive assessments. A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 previously identified AD-related polymorphisms. A genetic risk score for hearing (hearing-GRS) was calculated using 3 previously identified polymorphisms related to hearing impairment. Using age-, sex-, and genetic ancestry-adjusted logistic and linear regression models, we evaluated whether the AD-GRS predicted poor hearing and whether the hearing-GRS predicted worse cognition. Poor speech-in-noise hearing (>-5.5-dB speech reception threshold; prevalence 14%) was associated with lower cognitive scores (ß = -1.28; 95% confidence interval [CI] -1.54 to -1.03). Higher AD-GRS was significantly associated with poor speech-in-noise hearing (odds ratio [OR] 1.06; 95% CI 1.01-1.11) and self-reported problems hearing with background noise (OR 1.03; 95% CI 1.00-1.05). Hearing-GRS was not significantly associated with cognitive scores (ß = -0.05; 95% CI -0.17 to 0.07). Genetic risk for AD also influences speech-in-noise hearing. We failed to find evidence that genetic risk for hearing impairment affects cognition. AD disease processes or a that shared etiology may cause speech-in-noise difficulty before dementia onset.

Descriptive study of workplace demand, control and bullying among migrant and Australian-born workers by gender: does workplace support make a difference?

ObjectiveThe objective of this study is to examine the relationship between bullying in migrants and Australians and types of workplace Iso-strain, by gender.Design and settingTwo descriptive cross-sectional surveys of the Australian working population.ParticipantsAustralian-born workers of Caucasian ancestry (n=1051, participant response rate=87.3%) and workers born in New Zealand (n=566), India (n=633) and the Philippines (n=431) (participant response rate=79.5%).Primary and secondary outcomes measuresUsing logistic regression, we examined whether self-reported assessment of various forms of bullying in the workplace was associated with Iso-strain (job with high demands and low control and without social support), gender and migrant status.ResultsThe prevalence of workplace bullying within the previous year was 14.5%. Sexual harassment, though rare (n=47, 1.8%), was reported by more women than men (83% vs 17%, χ2=19.3, p<0.0001) and more Australia or New Zealand born workers compared to India or the Philippines workers (75.5% vs 25.5%, χ2=4.6, p=0.032). Indian-born women had lower adjusted OR for being bullied and for being intimidated compared to other women. Independent of migrant status, Iso-strain (1), (low support from boss) and Iso-strain (2), (low support from colleagues) predicted being bullied. Women were more likely to be in an Iso-strain (1) job than men (18.7% vs 13.6%, p=0.013) and had twice the risk of being both verbally abused and intimidated compared to men (OR 9 vs OR 5.5, p<0.0001).ConclusionWorkplace bullying was more likely for women than men. There were few differences between workers from different migrant groups. Iso-strain was the strongest predictor of workplace bullying. Workplaces should encourage supportive and collegiate work environments.

1152 Genetic Risk Of Alzheimer’S Disease Is Linked To Short Sleep Duration

Abstract Introduction Sleep disturbances including short sleep duration are common in older adults, especially in those with Alzheimer’s disease (AD). However, it is unclear to what extent sleep duration is a manifestation of AD disease process. We examined whether genetic variants related to AD influence sleep duration in middle-aged and older adults and estimated the causal effects of AD on sleep duration using a mendelian randomization (MR) analysis. Methods We examined 406,687 UK Biobank participants with Caucasian genetic ancestry who self-reported sleep duration at baseline (2006-2010). Sleep duration was assessed by asking: “About how many hours sleep do you get in every 24 hours? (please include naps).” A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 previously identified AD-related single nucleotide polymorphisms in individuals of European ancestry. We evaluated whether AD-GRS predicted sleep duration using linear regression, adjusting for age, sex and principle components for genetic ancestry. We also stratified the analysis by age at baseline (≤55y or &amp;gt;55y) and conducted a MR analysis to estimate the effect of AD (ICD-9/10 codes for AD/dementia diagnosis) on sleep duration. Results The participants (aged 56.91±8.00y) had an average sleep duration of 7.2 (Standard deviation [SD]=1.1) hours and AD-GRS of 0.11 (SD=0.40) (range: -1.15~1.85). Higher AD-GRS score predicted shorter sleep duration (b= -0.013, 95%CI:-0.022,-0.005), mainly among those aged over 55y (b= -0.023, 95%CI:-0.034,-0.012) and not in those 55y or younger (b= 0.006, 95%CI:-0.012,0.013); p for interaction by age=0.02. MR analysis using AD-GRS as an instrumental variable suggested that AD was associated with 1.76 hrs (b=-1.76, -2.62~ -0.90) shorter sleep duration in those aged &amp;gt;55y. Conclusion Using a novel analytical approach, we found that higher genetic risk for AD predicted shorter sleep duration among older adults. This suggests shared genetic pathways; the biologic processes that lead to AD may also affect sleep duration. Support Dr. Leng received support from the National Institute on Aging (NIA) 1K99AG056598, and from GBHI, Alzheimer’s Association, and Alzheimer’s Society (GBHI ALZ UK-19-591141).

Genetic Susceptibility to Clozapine-Induced Agranulocytosis/Neutropenia Across Ethnicities: Results From a New Cohort of Turkish and Other Caucasian Participants, and Meta-Analysis

Abstract Clozapine (CLZ) is considered the most effective antipsychotic, but its use is associated with neutropenia (CIN) and agranulocytosis (CIA). Although the exact etiology of these hazardous side effects is unknown, 4 genetic polymorphisms have been implicated by genome-wide association studies (GWAS), mostly performed in North-Western Europeans. These polymorphisms are rs113332494 (HLA-DQB1), rs41549217 (HLA-B), and rs1546308/rs149104283 (SLCO1B3/7), several of which were not directly genotyped but imputed. To test whether these 4 single-nucleotide polymorphisms (SNPs) are associated with CIN/CIA in a Turkish population and in a more extensive group of Caucasians, we directly genotyped these polymorphisms using Taqman and Sanger sequencing and performed logistic regression. We divided our participants (234 CLZ-using participants of whom 31 CIN/CIA cases) into (1) North-Western European, (2) Turkish, (3) Caucasian (=1 + 2); and (4) a total group (Caucasian + other ethnicities). Rs113332494 (HLA-DQB1) was significantly associated with CIN/CIA in the total group (P = 3.5 × 10−8), in the Caucasian group (P = 9.3 × 10−6) and in the Turkish group (P = 2.8 × 10−5). Rs41549217 (HLA-B) was nominally significant in the Caucasian group (P = .018). In meta-analysis of our results and the previously reported genome-wide results, 3 SNPs were significantly associated with CIN/CIA in participants with Caucasian ancestry: rs113332494 (P = 2.05 × 10−8), rs41549217 (P = 7.19 × 10−9), and rs149104283 (P = 5.54 × 10−9), with the result for rs1546308 (SCLO1B3/SCLO1B7) being significantly heterogeneous across studies. Our results hint at ethnicity-dependent and clinically relevant effects of genetic polymorphisms on the risk to develop CIN/CIA. Pharmacogenetic testing can complement clinical decision making and thus empower appropriate CLZ prescribing, but ancestry should be taken into account when performing such testing for CLZ.

GENOME-WIDE META-ANALYSIS SUPPORTS HETEROGENEITY IN POLYGENIC ARCHITECTURE OF DISABILITY

Disability and frailty increase steeply with age after midlife. They comprise broad, non-specific aging-related health/well-being declines. Understanding the molecular mechanisms of these declines could help in combating processes related to intrinsic aging. We performed genome-wide meta-analysis of disability using data on N=12,550 disabled individuals of Caucasian ancestry from five independent studies with N=24,068 genotyped participants. Disability was measured using the Activities of Daily Living (ADL) scale. A subject was considered disabled if he/she had at least one ADL impairment. All subjects in our study were aged 50+ years. The analysis followed a discovery-replication strategy using two studies as discovery samples and three others as replication samples. At the discovery stage, we selected SNPs at nominal significance (p<0.05) and evaluated their associations with disability in the replication samples. Meta-analysis across all studies identified 30 SNPs (24 loci) at p<10e-4. SNPs from four loci (chromosomes 2, 8, and 12) attained suggestive significances at p<10-5. We constructed two polygenic risk scores (PGRS) using these 30 SNPs whose minor alleles were positively (19 SNPs) and negatively (11 SNPs) associated with disability, PGRS_p and PGRS_n, respectively. Meta-analysis across all studies identified strong effects for PGRS_p (beta=0.436, p=1.18×10e-32) and PGRS_n (beta=-0.426, p=8.74×10e-19). The associations for the PGRSs observed in two discovery studies were replicated in three independent studies. The lack of genome-wide significant effects of individual SNPs combined with the highly significant effects of the PGRSs shows that, in line with the heterogeneous origin of disability, its genetic architecture is of highly heterogeneous polygenic origin.

Black African and Latino/a identity correlates with increased plasmablasts in MS.

ObjectiveTo determine the influence of self-reported Black African and Latin American identity on peripheral blood antibody-secreting cell (ASC) frequency in the context of relapsing-remitting MS.MethodsIn this cross-sectional study, we recruited 74 subjects with relapsing-remitting MS and 24 age-, and self-reported ethno-ancestral identity-matched healthy donors (HDs) to provide peripheral blood study samples. Subjects with MS were either off therapy at the time of study draw or on monthly natalizumab therapy infusions. Using flow cytometry, we assessed peripheral blood mononuclear cells for antibody-secreting B-cell subsets.ResultsWhen stratified by self-reported ethno-ancestry, we identified significantly elevated frequencies of circulating plasmablasts among individuals with MS identifying as Black African or Latin American relative to those of Caucasian ancestry. Ethno-ancestry–specific differences in ASC frequency were observed only among individuals with MS. By contrast, this differential was not observed among HDs. ASCs linked with poorer MS prognosis and active disease, including IgM+- and class-switched CD138+ subsets, were among those significantly increased.ConclusionThe enhanced peripheral blood plasmablast signature revealed among Black African or Latin American subjects with MS points to distinct underlying mechanisms associated with MS immunopathogenesis. This dysregulation may contribute to the disease disparity experienced by patient populations of Black African or Latin American ethno-ancestry.

Full blood count and white cell differential count reference ranges obtained from a healthy urban South African population residing in the Western Cape of South Africa.

Research has suggested that individuals of African descent have lower white cell and neutrophil counts than Caucasians. These differences could lead to incorrect clinical decisions, and therefore, ethnic-specific reference ranges are required. The Western Cape region of South Africa is uniquely diverse, comprising Caucasian, Mixed Ancestry and those of African descent. The aim of this study was to compare the full blood count and differential counts across the three major ethnic groups residing in this area and to propose appropriate RIs. The study formed part of the international project led by the Committee on Reference Intervals and Decision Limits (C-RIDL), and therefore, the strict guidelines laid out by the committee were followed. Full blood count and differential counts were performed on a Beckman Coulter ACT 5 diff AL analyser within 2-4hours of collection and were reported as mean (standard deviation), 2.5th and 97.5th percentiles. Comparisons were analysed using Spss v25 and Statistica v13, and a P value of<0.05 was considered significant. Reference ranges for Caucasian and Mixed Ancestry individuals were similar while white cell (P=0.016), monocyte (P<0.001), neutrophil (P=0.034) and red cell indices were significantly different amongst the three population groups. There were however no statistical and clinical significant differences between the eosinophil, lymphocyte, red cell and platelet counts across the three groups. In conclusion, subjects of Mixed Ancestry, in this region, have similar reference intervals to those of European descent, while lower white cell and neutrophil counts in Africans have been confirmed.

Abstract 1583: Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development

Abstract The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43(OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. We further explored the impact of identified genetic interactions on the expression of involved cancer-related genes using the lung eQTL dataset including a total of 409 subjects with both genotyping and gene expression data. In the study between TSPAN8 gene and rs1882898:rs1705235 SNP pair, we identified decreased gene expression in individuals with reduced lung cancer risk which supports the oncogene function of TSPAN8. In the gene expression analysis between SYNE1 and rs10515157:rs1554783 SNP pair, we also identified consistent evidence between gene expression and lung cancer risk. Finally, we conducted gene set enrichment analysis to reveal potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play important roles in lung tumorigenesis. Epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes. Citation Format: Yafang Li, Xiangjun Xiao, Ivan Gorlov, Younghun Han, Rayjean Hung, Christopher Amos. Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1583.

Safety and efficacy of edaravone compared to historical controls in patients with amyotrophic lateral sclerosis from North-Eastern Italy

ObjectiveTo test efficacy and tolerability of edaravone in patients with amyotrophic lateral sclerosis (ALS) originating from North-Eastern Italy. MethodsWe compared 3-month and 6-month changes of ALSFRS-R score, FVC value, and MRC score of 31 consecutive patients with ALS who were treated with edaravone to those of 50 historical ALS patients who were not treated with edaravone. ResultsNo significant difference for any functional measures was found between the two groups at each time point as compared to baseline. In treated patients, we also observed creatinine values to significantly decrease at 3 and 6 months (p = 0.0078 and 0.030, respectively) and ALSAQ5 score to significantly increase (i.e. worse quality of life) at 3 and 6 months (p = 0.0005 and 0.0078, respectively). Yet, we observed an overall safety of the medication over the 6-month period of observation. ConclusionsOur retrospective study suggests no benefit of edaravone on ALS in populations of Caucasian ancestry.

Association of variants of prodynorphin promoter 68-bp repeats in caucasians with opioid dependence diagnosis: Effect on age trajectory of heroin use

The dynorphin/kappa opioid receptor (Dyn/KOR) system is involved in reward processing and dysphoria/anhedonia. Exposure to mu-opioid receptor agonists such as heroin increases expression of the prodynorphin gene (PDYN) in the brain. In this study in a Caucasian cohort, we examined the association of the functional PDYN 68-bp repeat polymorphism with opioid use disorders. In this case-control study, 554 subjects with Caucasian ancestry (142 healthy controls, 153 opioid-exposed, but never opioid dependent, NOD, and 259 with an opioid dependence diagnosis, OD) were examined for association of the PDYN 68-bp repeats with the diagnosis of opioid dependence (DSM-IV criteria), with a dimensional measure of heroin exposure (KMSK scale), and age trajectory parameters of heroin use (age of heroin first use, and age of onset of heaviest use). The PDYN 68-bp repeat genotype (classified as: “short-short” [SS], “long-long” [LL], and “short-long” [SL], based on the number of repeats) was not associated with categorical opioid dependence diagnoses. However, the LL genotype was associated with later age of first heroin use than the SS + SL genotype (19 versus 18 years; p < 0.01). This was also confirmed by a significant positive correlation between the number of repeats and the age of first use of heroin, in volunteers with OD (Spearman r = 0.16; p = 0.01). This suggests that the functional PDYN 68-bp repeat genotype is associated with the age of first use of heroin in Caucasians diagnosed with opioid dependence.

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

Abstract P1-10-01: Defining the spectrum of germline variants among African American patients with triple negative breast cancer

Abstract Background: African American (AA) women are more likely to have breast cancer at a younger age and be diagnosed with triple negative breast cancer (TNBC), which is as yet unexplained. We examined results of multi-gene panel testing in AA women with TNBC tested at a large commercial laboratory to assess the utility of gene panels and findings in this group. Methods: We assessed individuals who had clinical hereditary cancer testing with a multi-gene panel between September 2013 and May 2018. Women were included for analysis if they had a personal history of TNBC and self-identified as having any AA ancestry (n=3,268) or only Caucasian (CA) ancestry (n=8,953). Clinical data was collected from provider-completed test request forms. Comparisons were performed using descriptive statistics, t-tests (continuous variables), and chi-square tests (categorical variables) adjusting for multiple testing when necessary. Results: In this cohort, AA women were significantly more likely than CA women to meet NCCN guidelines (97.5% vs. 96.6%, p=0.010) and significantly less likely to have an additional personal (16.2% vs. 21.8%, p&amp;lt;0.001) or family (79.3% vs. 86.3%, p&amp;lt;0.001) history of cancer. Overall, 11.5% of AA women were found to carry a pathogenic variant (PV) compared to 13.4% of CA women (p=0.004; Table 1). Compared to CA women, AA women with a PV were significantly younger at diagnosis (46.7 vs. 49.5 years of age; p&amp;lt;0.001). The prevalence of PVs in BRCA1, CHEK2 and the Lynch syndrome genes was higher in CA women, whereas the prevalence of BRCA2 PVs was higher in AA women. While the prevalence of PVs in individual genes was not significantly different according to ancestry after adjusting for multiple comparisons, AA women were significantly less likely to have a PV in any breast cancer-related gene compared to CA women (p=0.048). AA women were significantly more likely to have a Variant of Uncertain Significance (VUS; 35.6% vs. 20.9%; p&amp;lt;0.001) and to have &amp;gt;1 VUS (8.6% vs. 2.6%, p&amp;lt;0.001). Regardless of ancestry, patients diagnosed before age 40 were more likely to carry a PV (19.7% AA, 22.2% CA). However, the prevalence of PVs among patients diagnosed after age 60 was still striking (8.9% AA, 10.9% CA) and was similar to the PV prevalence among patients diagnosed between 40-60 (10.1% AA, 12.3% CA). Conclusions: In the era of multi-gene panel testing, this large cohort of patients with TNBC supports the use of panel testing in AA women with TNBC regardless of age or additional personal/family history of cancer. While additional research to the rate and pathogenicity of VUS in AA women is needed, genetic counseling is necessary to explain the possibility and meaning of a VUS in this group. Table 1.Distribution of PVs in BC-related genes according to ancestry AA WomenCA WomenGeneN (%)N (%)Any Breast Cancer-Related Gene347 (10.6)1104 (12.3)BRCA1132 (4.0)496 (5.5)BRCA297 (3.0)236 (2.6)ATM6 (0.2)25 (0.3)BARD119 (0.6)67 (0.7)BRIP120 (0.6)46 (0.5)CDH11 (&amp;lt;0.1)1 (&amp;lt;0.1)CHEK22 (0.1)33 (0.4)NBN2 (0.1)10 (0.1)PALB244 (1.3)138 (1.5)PTEN2 (0.1)4 (&amp;lt;0.1)RAD51C20 (0.6)41 (0.5)STK1101 (&amp;lt;0.1)TP532 (0.1)6 (0.1)Lynch Syndrome Genes10 (0.3)46 (0.5)Other Genes12 (0.4)24 (0.3)Multiple PVs6 (0.2)28 (0.3)Total (Any Gene)375 (11.5)1202 (13.4) Citation Format: Pederson HJ, Heald B, Budd GT, Bernhisel R, Cummings S, Saam JR, Lancaster JM, Grobmyer SR, Eng C. Defining the spectrum of germline variants among African American patients with triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-10-01.

Candidate gene analyses for acute pain and morphine analgesia after pediatric day surgery: African American versus European Caucasian ancestry and dose prediction limits.

Acute pain and opioid analgesia demonstrate inter-individual variability and polygenic influence. In 241 children of African American and 277 of European Caucasian ancestry, we sought to replicate select candidate gene associations with morphine dose and postoperative pain and then to estimate dose prediction limits. Twenty-seven single nucleotide polymorphisms (SNPs) from 9 genes (ABCB1, ARRB2, COMT, DRD2, KCNJ6, MC1R, OPRD1, OPRM1, UGT2B7) met selection criteria and were analyzed along with TAOK3. Few associations replicated: morphine dose (mcg/kg) in African American children and ABCB1 rs1045642 (A allele, ß=−9.30, 95% CI −17.25–−1.35, p=0.02) and OPRM1 rs1799971 (G allele, ß=23.19, 95% CI 3.27–43.11, p=0.02); KCNJ6 rs2211843 and high pain in African American subjects (T allele, OR 2.08, 95% CI 1.17–3.71, p=0.01) and in congruent European Caucasian pain phenotypes; and COMT rs740603 for high pain in European Caucasian subjects (A allele, OR 0.69, 95% CI 0.48–0.99, p=0.046). With age, body mass index, and physical status as covariates, simple top SNP candidate gene models could explain theoretical maximums of 24.2% (European Caucasian) and 14.6% (African American) of morphine dose variances.

Biological insights into multiple birth: genetic findings from UK Biobank.

The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. We performed a genome-wide association study (GWAS) in 8962 participants with Caucasian ancestry from UK Biobank who reported being part of a multiple birth, and 409,591 singleton controls. We replicated the association between FSHB, SMAD3 and twinning in the gene-based (but not SNP-based) test, which had been established in previous genome-wide association analyses in mothers with dizygotic twin offspring. Additionally, we report a novel genetic variant associated with multiple birth, rs428022 at 15q23 (p = 2.84 × 10-8) close to two genes: PIAS1 and SKOR1. Finally, we identified meaningful genetic correlations between being part of a multiple birth and other phenotypes (anthropometric traits, health-related traits, and fertility-related measures). The outcomes of this study provide important new insights into the genetic aetiology of multiple births and fertility, and open up novel directions for fertility and reproduction research.

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer\u2019s disease

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer’s disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

Rare variants in Protein tyrosine phosphatase, receptor type A (PTPRA) in schizophrenia: Evidence from a family based study

The contribution of both common and rare risk variants to the genetic architecture of schizophrenia (SZ) has been documented in genome-wide association studies, whole exome and whole genome sequencing approaches. As SZ is highly heritable and segregates in families, highly penetrant rare variants are more likely to be identified through analyses of multiply affected families. Further, much of the gene mapping studies in SZ have utilized individuals of Caucasian ancestry. Analysis of other ethnic groups may be informative. In this study, we aimed at identification of rare, penetrant risk variants utilizing whole exome sequencing (WES) in a three-generation Indian family with multiple members affected. Filtered data from WES, combined with in silico analyses revealed a novel heterozygous missense variant (NM_080841:c.1730C>G:p.T577R; exon18) in Protein tyrosine phosphatase, receptor type A (PTPRA 20p13). The variant was located in an evolutionarily conserved position and predicted to be damaging. Screening for variants in this gene in the WES data of an independent SZ cohort (n = 350) of matched ethnicity, identified five additional rare missense variants with MAF < 0.003, which were also predicted to be damaging. In conclusion, the rare missense variants in PTPRA identified in this study could confer risk for SZ. This has also derived support from concordant data from prior linkage and association, as well as animal studies which indicated a role for PTPRA in glutamate function.

Linear Predictors of Facial Rotation Pattern in Croatian Subjects with Skeletal Class III Malocclusion.

ObjectivesThe objective of this study was to determine whether the linear measures of the maxilla, mandible and cranial base were predictors of facial growth rotation in a Croatian population with Class III malocclusion by cephalometric radiographic methods.Material and methodsThe examined sample consisted of pretreatment lateral cephalometric records of 201 (111 females and 90 males) untreated Class III patients of Caucasian Croatian ancestry from the Department of Orthodontics at Zagreb University. The measurements were divided into five categories for analysis: cranial base, skeletal maxillary and skeletal mandibular relationships, sagittal intermaxillary and vertical relationships. Five multiple linear regression models were used to identify predictors of facial rotation pattern.ResultsThe effective length of the mandible was the most important predictor of facial rotation pattern, with the increased length largerly predisposing the tendency to the vertical growth pattern. No significant dichotomy was found regarding gender apart from the fourth model in which the posterior rotation of maxilla is related to female gender.ConclusionThese predictors could help orthodontists determine timing and therapy for Croatian patients with Class III malocclusions.