Abstract 4267: Association of polygenic risk scores and family history with the risk of chronic lymphocytic leukemia (CLL)

ABSTRACTPolygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their clinical applicability. We set out to study how PRS could help in clinical decision making. Among 99,969 women in the FinnGen study with 6,879 breast cancer cases, the PRS was associated not only with breast cancer incidence but also with a range of breast cancer-related endpoints. Women with a breast cancer PRS above the 90th percentile had both higher breast cancer mortality (HR 2.40, 95%CI 1.82-3.17) and higher risk for non-localized disease at diagnosis (HR 2.94, 95%CI 2.63-3.28), compared to those with PRS <80th percentile. The PRS modified the breast cancer risk of two high-impact frameshift risk variants. Women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 263 carriers) and an average PRS (20-80th percentile) had a lifetime risk of breast cancer at 58% (95%CI 50-66%), which increased to 85% (70-100%) with a high PRS (>90th percentile), and decreased to 27% (15-39%) with a low PRS (<20th percentile). Similarly, for c.1100delC in CHEK2 (3.7-fold enrichment; 1,543 carriers), the respective lifetime risks were 27% (95%CI 25-30%), 59% (52-67%), and 18% (13-22%). Among breast cancer cases, a PRS >90th percentile was associated with risk of contralateral breast cancer with HR 1.66 (95%CI 1.24-2.22). Finally, the PRS significantly refined the risk assessment of women with first-degree relatives diagnosed with breast cancer, i.e. the combination of high PRS (>90th percentile) and a positive family-history was associated with a 2.33-fold elevated risk (95%CI 1.57-3.46) compared to a positive family history alone. These findings demonstrate opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members.

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Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Blood ◽

10.1182/blood-2017-11-814608 ◽

2018 ◽

Vol 131 (23) ◽

pp. 2541-2551 ◽

Cited By ~ 9

Author(s):

Geffen Kleinstern ◽

Nicola J. Camp ◽

Lynn R. Goldin ◽

Celine M. Vachon ◽

Claire M. Vajdic ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Risk Score ◽

Clinical Impact ◽

Lymphocytic Leukemia ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Key Points ◽

High Discrimination

Key Points PRS, based on the known CLL loci, predicts CLL risk with high discrimination. This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.

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Incorporating family history of disease improves polygenic risk scores in diverse populations

10.1101/2021.04.15.439975 ◽

2021 ◽

Author(s):

Margaux L.A. Hujoel ◽

Po-Ru Loh ◽

Benjamin M. Neale ◽

Alkes L. Price

Keyword(s):

Family History ◽

Threshold Model ◽

South Asians ◽

Target Population ◽

Risk Scores ◽

Diverse Populations ◽

Polygenic Risk ◽

History Of Disease ◽

History Of ◽

Large Improvement

AbstractPolygenic risk scores derived from genotype data (PRS) and family history of disease (FH) both provide valuable information for predicting disease risk, enhancing prospects for clinical utility. PRS perform poorly when applied to diverse populations, but FH does not suffer this limitation. Here, we explore methods for combining both types of information (PRS-FH). We analyzed 10 complex diseases from the UK Biobank for which family history (parental and sibling history) was available for most target samples. PRS were trained using all British individuals (N=409K), and target samples consisted of unrelated non-British Europeans (N=42K), South Asians (N=7K), or Africans (N=7K). We evaluated PRS, FH, and PRS-FH using liability-scale R2, focusing on three well-powered diseases (type 2 diabetes, hypertension, depression) with R2 > 0.05 for PRS and/or FH in each target population. Averaging across these three diseases, PRS attained average prediction R2 of 5.8%, 4.0%, and 0.53% in non-British Europeans, South Asians, and Africans, confirming poor cross-population transferability. In contrast, PRS-FH attained average prediction R2 of 13%, 12%, and 10%, respectively, representing a large improvement in Europeans and an extremely large improvement in Africans; for each disease and each target population, the improvement was highly statistically significant. PRS-FH methods based on a logistic model and a liability threshold model performed similarly when covariates were not included in predictions (consistent with simulations), but the logistic model outperformed the liability threshold model when covariates were included. In conclusion, including family history greatly improves the accuracy of polygenic risk scores, particularly in diverse populations.

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Delineating genetic and familial risk for psychopathology in the ABCD study

10.1101/2020.09.08.20186908 ◽

2020 ◽

Author(s):

Clare E Palmer ◽

Robert John Loughnan ◽

Carolina Makowski ◽

Wesley Thompson ◽

Deanna Barch ◽

...

Keyword(s):

Family History ◽

Psychiatric Disorders ◽

Genetic Risk ◽

Familial Risk ◽

Risk Scores ◽

Typically Developing ◽

Polygenic Risk ◽

Hyperactivity Disorder ◽

History Of ◽

Risk Predictors

Psychiatric disorders place a huge burden on those affected and their families, as well as society. Nearly all psychiatric disorders have a heritable component and lifetime prevalence rates of several disorders are higher among first degree biological relatives of individuals with a diagnosis. Given that many psychiatric disorders have their onset in adolescence, estimating genetic risk during childhood may identify at-risk individuals for early intervention that can reduce this burden. Here we measured genetic risk for psychopathology using both polygenic risk scores (PRS) and family history in a large typically developing sample of 9-10 year old children from the Adolescent Brain and Cognitive Development (ABCD) StudySM and determined associations with a large battery of behavioural phenotypes. By including all genetic risk predictors in the same model, we were able to delineate unique behavioral associations across these measures. Polygenic risk for Attention Deficit Hyperactivity Disorder (ADHD) and depression (DEP) was associated with unique patterns of both externalizing and internalizing behaviors. Family history of conduct problems, depression and anxiety/stress additionally predicted unique behavioral variance across similar measures. These findings provide important insight into the potential predictive utility of PRS and family history in early adolescence and suggest that they may be signaling differential, additive information that could be useful for quantifying risk during development.

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Heterogeneity of the Predictive Polygenic Risk Scores for Coronary Heart Disease Age-at-onset in Three Different CHD Family-based Ascertainments

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003201 ◽

2021 ◽

Author(s):

Mary F. Feitosa ◽

Allison L. Kuipers ◽

Mary K. Wojczynski ◽

Lihua Wang ◽

Emma Barinas-Mitchell ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Family History ◽

High Risk ◽

Healthy Aging ◽

Age At Onset ◽

Risk Scores ◽

Polygenic Risk ◽

Chd Risk ◽

Family Based

Background - Polygenic risk scores (PRS) for coronary heart disease (CHD) may contribute to assess the overall risk of CHD. We evaluated how PRS may influence CHD risk when the distribution of age-at-onset, sex, and family health history differ significantly. Methods - Our study included three family-based ascertainments: Long Life Family Study (LLFS, N Individuals =4,572), which represents a low CHD risk, and Family Heart Study, which consists of randomly selected families (FamHS-Random, N Individuals =1,806), and high CHD risk families (FamHS-High Risk, N Individuals =2,301). We examined the effects of PRS, sex, family ascertainment, PRS interaction with sex (PRS*Sex) and with family ascertainment (PRS*LLFS and PRS*FamHS-High Risk) on CHD, corrected for traditional cardiovascular risk factors using Cox proportional hazard regression models. Results - Healthy-aging LLFS presented ~17 years delayed for CHD age-at-onset compared with FamHS-High Risk ( P <1.0x10 -4 ). Sex-specific association ( P <1.0x10 -17 ) and PRS*Sex ( P =2.7x10 -3 ) predicted prevalent CHD. CHD age-at-onset was associated with PRS (HR=1.57, P =1.3x10 -5 ), LLFS (HR=0.54, P =2.6x10 -5 ) and FamHS-High Risk (HR=2.86, P =6.70x10 -15 ) in men, and with PRS (HR=1.76, P =7.70x10 -3 ), FamHS-High Risk (HR=4.88, P =8.70x10 -10 ) and PRS*FamHS-High Risk (HR=0.61, P =3.60x10 -2 ) in women. In the PRS extreme quartile distributions, CHD age-at-onset was associated ( P <0.05) with PRS, FamHS-High Risk, and PRS interactions with both low and high CHD risk families for women. For men, the PRS quartile results remained similar to the whole distribution. Conclusions - Differences in CHD family-based ascertainments show evidence of PRS interacting with sex to predict CHD risk. In women, CHD age-at-onset was associated with PRS, CHD family history, and interactions of PRS with family history. In men, PRS and CHD family history were the major effects on the CHD age-at-onset. Understanding the heterogeneity of risks associated with CHD endpoints at both the personal and familial levels may shed light on the underlying genetic effects influencing CHD and lead to more personalized risk prediction.

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The association of polygenic risk for schizophrenia, bipolar disorder, and depression with neural connectivity in adolescents and young adults: examining developmental and sex differences

Translational Psychiatry ◽

10.1038/s41398-020-01185-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

J. L. Meyers ◽

D. B. Chorlian ◽

T. B. Bigdeli ◽

E. C. Johnson ◽

F. Aliev ◽

...

Keyword(s):

Young Adults ◽

Sex Differences ◽

Family History ◽

Collaborative Study ◽

Adolescents And Young Adults ◽

Risk Scores ◽

Eeg Coherence ◽

Neural Connectivity ◽

Polygenic Risk ◽

History Of

AbstractNeurodevelopmental abnormalities in neural connectivity have been long implicated in the etiology of schizophrenia (SCZ); however, it remains unclear whether these neural connectivity patterns are associated with genetic risk for SCZ in unaffected individuals (i.e., an absence of clinical features of SCZ or a family history of SCZ). We examine whether polygenic risk scores (PRS) for SCZ are associated with functional neural connectivity in adolescents and young adults without SCZ, whether this association is moderated by sex and age, and if similar associations are observed for genetically related neuropsychiatric PRS. One-thousand four-hundred twenty-six offspring from 913 families, unaffected with SCZ, were drawn from the Collaborative Study of the Genetics of Alcoholism (COGA) prospective cohort (median age at first interview = 15.6 (12–26), 51.6% female, 98.1% European American, 41% with a family history of alcohol dependence). Participants were followed longitudinally with resting-state EEG connectivity (i.e., coherence) assessed every two years. Higher SCZ PRS were associated with elevated theta (3–7 Hz) and alpha (7–12 Hz) EEG coherence. Associations differed by sex and age; the most robust associations were observed between PRS and parietal-occipital, central-parietal, and frontal-parietal alpha coherence among males between ages 15–19 (B: 0.15–0.21, p < 10–4). Significant associations among EEG coherence and Bipolar and Depression PRS were observed, but differed from SCZ PRS in terms of sex, age, and topography. Findings reveal that polygenic risk for SCZ is robustly associated with increased functional neural connectivity among young adults without a SCZ diagnosis. Striking differences were observed between men and women throughout development, mapping onto key periods of risk for the onset of psychotic illness and underlining the critical importance of examining sex differences in associations with neuropsychiatric PRS across development.

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Abstract 3453: Medical history, lifestyle, and family history exposures and chronic lymphocytic leukemia outcome

10.1158/1538-7445.am2016-3453 ◽

2016 ◽

Author(s):

Sara Beiggi ◽

James M. Foran ◽

O’Byrne Megan ◽

Celine M. Vachon ◽

Timothy G. Call ◽

...

Keyword(s):

Family History ◽

Chronic Lymphocytic Leukemia ◽

Medical History ◽

Lymphocytic Leukemia

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