Genetic Analysis Reveals Rare Variants in T-Cell Response Gene MR1 Associated with Poor Overall Survival after Urothelial Cancer Diagnosis

Urothelial carcinoma of the bladder (UC) is the fifth most common cancer in the United States. Germline variants, especially rare germline variants, may account for a portion of the disparity seen among patients in terms of UC incidence, presentation, and outcomes. The objectives of this study were to identify rare germline variant associations in UC incidence and to determine its association with clinical outcomes. Using exome sequencing data from the DiscovEHR UC cohort (n = 446), a European-ancestry, North American population, the complex influence of germline variants on known clinical phenotypes were analyzed using dispersion and burden metrics with regression tests. Outcomes measured were derived from the electronic health record (EHR) and included UC incidence, age at diagnosis, and overall survival (OS). Consequently, key rare variant association genes were implicated in MR1 and ADGRL2. The Kaplan–Meier survival analysis reveals that individuals with MR1 germline variants had significantly worse OS than those without any (log-rank p-value = 3.46 × 10−7). Those with ADGRL2 variants were found to be slightly more likely to have UC compared to a matched control cohort (FDR q-value = 0.116). These associations highlight several candidate genes that have the potential to explain clinical disparities in UC and predict UC outcomes.

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Myelodysplastic Syndrome: A Study of VA Population.

Blood ◽

10.1182/blood.v110.11.2470.2470 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2470-2470 ◽

Cited By ~ 2

Author(s):

Gina M. Matacia-Murphy ◽

Najla H. Al Ali ◽

Jeffrey A. Schrager ◽

M.S. Beg ◽

Malek M. Safa ◽

...

Keyword(s):

Overall Survival ◽

Treatment Options ◽

Large Population ◽

Case Series ◽

The United States ◽

Refractory Anemia ◽

Categorical Variables ◽

P Value ◽

Medical Centers ◽

Seer Data

Abstract Background: Epidemiology and outcome of myelodysplastic syndromes (MDS) in the United States is not well recognized. MDS became reportable to the Surveillance, Epidemiology, and End Results program (SEER) in 2001. Only one study is published examining the SEER data between 2001–2003 on MDS incidence, epidemiology and outcome. We report first study of MDS among large population in the Veteran Affair system. Methods: There are approximately 127 VA Medical Centers diagnosing and/or treating Cancer patients. The data collected by the medical centers cancer registries is aggregated as the VA Central Cancer Registry (VACCR) and is maintained by the Chief Program Office for Oncology at VA in Washington DC. We used the VACCR to analyze VA patients with MDS diagnosed between 1995 and 2005. The data was downloaded from the database using ICD-03 histology codes for MDS. Data was entered and analyzed using bio-statistical software SPSS. Kaplan-Meier curves were used for estimates of overall survival, chi square for comparison of categorical variables and t-test for continuous variables. Results: Between 1995 and 2005, 1411 MDS cases were registered in the VACCR database. The median age was 75 years. Among those 1379 (97.7%) were males and 1196 (84.4%) were white patients, 171 (12.1%) black, and 44 (3.5%) other race. Majority of cases were reported as MDS, NOS 935 (66.3%), Refractory anemia (RA) 180 (12.8%), Refractory anemia with ring sideroblasts (RARS) 105 (7.4%), Refractory anemia with multilineage dysplasia (RCMD) 22 (1.6%), 5 q syndrome 13 (0.9%), Refractory anemia with excess blasts (RAEB) 105 (7.4%), Refractory anemia with excess blast in transformation 17 (1.2%), and therapy related MDS (t-MDS) 34 (2.4%). No IPSS data were available. The median overall survival (OS) was 1.8 year (95% CI 1.5–2.1). The 3 year and 5 year overall survival was 30% and 22% respectively. The median OS for RA patients was 3.7 year, RARS 4.9 year and for RAEB was 0.8 year. No difference was observed in OS between whites and black (median OS 1.73 versus 2.65, p value 0.28). Their was a non statistically significant trend for improvement of OS in patients diagnosed in 2004–2005 compared to 1995–2003 (time where azacitidine and lenalidomide were approved) median OS of 3.2 versus 1.8 (p value 0.64). Conclusion: This is the first report of MDS case series in the VA system. Outcome is similar to what is described in literature and SEER data (3 Year OS was 30% in our VA population study compared to 35% in recently published SEER data). No racial disparities are observed in outcome. A trend towards better overall survival is noted in the last 2 years since approval of new treatment options. Coding for WHO subtypes, IPSS and treatment options should be considered in all large MDS registries.

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Impact of colonoscopy on patients older than 75.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15096 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15096-e15096

Author(s):

Dhauna Karam ◽

Mohammed Al-Hamadani ◽

Shah Pallavi ◽

Mohamed Shanshal ◽

Janos Molnar

Keyword(s):

United States ◽

Overall Survival ◽

Survival Time ◽

The United States ◽

Young Age ◽

Screening Colonoscopy ◽

Rank Test ◽

P Value ◽

Age Group ◽

Mean Survival Time

e15096 Background: Colorectal cancer is the second leading cause of cancer related deaths in the United States. As per current screening guidelines, screening should begin by age 50 and be continued till age 75. Routine screening over 75 years is not recommended. Methods: Our primary objective was to compare survival time in patients undergoing colonoscopy aged 75 years or older to those aged 50-74. The study was conducted at Captain James A. Lovell Federal Health Care Center (FHCC), North Chicago, United States between 2002 and 2012. A retrospective chart review was performed for patients who underwent colonoscopy. Mortality in terms of survival time was compared between patients equal or older than 75 versus those aged 50-74 years with similar procedural indications and life expectancy of 5 years or more. Survival analysis was performed via Kaplan Meier curve with log-rank test. Results: A total of 213 patients were included in the study . Fifty one percent of the patients (108) were 50-74 years old (young age group), while 49% (105) were 75 or older (old age group). Patients had colonoscopy done for following indications: 92 (43%) screening colonoscopy, 62 (29.1%) diagnostic colonoscopy and 59 (27.7%) surveillance colonoscopy. There was no statistical difference between the age groups based on indication of colonoscopy (P = 0.899). Overall mean survival time for all patients was 123.6 months (10.3 years). Survival time was significantly higher for young age group with a mean overall survival of 131.1 months (10.9 years). Older age group had a mean overall survival time of 106.9 months (8.9 years). P-value = 0.009. The highest overall mean survival time was observed in patients who were under 75 and had colonoscopy for screening purposes 138.9 months (11.6 years) (P = 0.019). The lowest overall mean survival time was seen in those who were > 75 years and had colonoscopy due to diagnostic purposes 93.6 months(7.8 years). (P = 0.055) Conclusions: Although statistically significant higher survival time was noted in patients younger than 75, older patients also had a survival time of more than 7 years. This will impact the decision to offer screening colonoscopy to older people who will definitely benefit from the test.

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Host genomics of the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment

10.1101/19013763 ◽

2019 ◽

Author(s):

Christian W. Thorball ◽

Alessandro Borghesi ◽

Nadine Bachmann ◽

Chantal von Siebenthal ◽

Valentina Vongrad ◽

...

Keyword(s):

Genetic Variation ◽

Decay Rate ◽

Antiretroviral Treatment ◽

Rare Variants ◽

European Ancestry ◽

Viral Reservoir ◽

Human Genetic Variation ◽

Sequencing Data ◽

Common Genetic Variants ◽

Hiv 1

ABSTRACTIntroductionA major hurdle to HIV-1 eradication is the establishment of a latent viral reservoir early after primary infection. Several factors are known to influence the HIV-1 reservoir size and decay rate on suppressive antiretroviral treatment (ART), but little is known about the role of human genetic variation.MethodsWe measured the reservoir size at three time points over a median of 5.4 years, and searched for associations between human genetic variation and two phenotypic readouts: the reservoir size at the first time point and its decay rate over the study period. We assessed the contribution of common genetic variants using genome-wide genotyping data from 797 patients with European ancestry enrolled in the Swiss HIV Cohort Study and searched for a potential impact of rare variants and exonic copy number variants using exome sequencing data generated in a subset of 194 study participants.ResultsGenome- and exome-wide analyses did not reveal any significant association with the size of the HIV-1 reservoir or its decay rate on suppressive ART.ConclusionsOur results point to a limited influence of human genetics on the size of the HIV-1 reservoir and its long-term dynamics in successfully treated individuals.

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Autosomal Recessive Alzheimer’s disease (arAD): homozygosity mapping of genomic regions containing arAD loci

10.1101/2020.02.10.941393 ◽

2020 ◽

Author(s):

Sonia Moreno-Grau ◽

Maria Victoria Fernández ◽

Itziar de Rojas ◽

Isabel Hernández ◽

Fabiana Farias ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Homozygosity Mapping ◽

European Ancestry ◽

P Value ◽

Sequencing Data ◽

Whole Exome ◽

Whole Exome Sequencing Data ◽

Genomic Regions ◽

Outbred Populations

ABSTRACTLong runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of recent inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD). However, the search for recessive variants has been poorly assessed to date. To investigate homozygosity in AD, we performed a fine-scale ROH analysis including 21,100 individuals from 10 cohorts of European ancestry (11,919 AD cases and 9,181 controls). We detected an increase of homozygosity in AD cases compared to controls [βFROH (CI95%) = 0.051 (0.023 – 0.078); P = 3.25 x 10-4]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 x 10-16). The top associated ROH with AD risk (β (CI95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 x 10-4) was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), previously related to AD. Next, to construct a homozygosity map of AD cases, we selected ROHs shared by inbred AD cases extracted from an outbred population. We used whole-exome sequencing data from 1,449 individuals from the Knight-ADRC-NIA-LOAD (KANL) cohort to identify potential recessive variants in candidate ROHs. We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.

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ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

10.1101/2020.04.03.20047977 ◽

2020 ◽

Cited By ~ 16

Author(s):

Benetti Elisa ◽

Tita Rossella ◽

Spiga Ottavia ◽

Ciolfi Andrea ◽

Birolo Giovanni ◽

...

Keyword(s):

Genetic Background ◽

Rare Variants ◽

Clinical Severity ◽

P Value ◽

Italian Population ◽

Sequencing Data ◽

Surface Binding ◽

Internalization Process ◽

Whole Exome Sequencing Data ◽

Novel Coronavirus

ABSTRACTIn December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus-disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries.It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for inter-individual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome-sequencing data of 6930 Italian control individuals from five different centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison of ACE2 WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value <0,029) higher allelic variability in controls compared to patients. These findings suggest that a predisposing genetic background may contribute to the observed inter-individual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.

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Bone Marrow Fibrosis Is a Not Predictor of Overall Survival in Patients with Myeloma.

Blood ◽

10.1182/blood.v106.11.5091.5091 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5091-5091

Author(s):

P. Roberts ◽

S. Paneesha ◽

H. Freeman ◽

G. Pratt ◽

N. Chachalani ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

P Value ◽

Bence Jones Protein ◽

Poor Overall Survival ◽

Β2 Microglobulin ◽

Fibre Network ◽

Line Of Therapy ◽

The Impact ◽

Marrow Fibrosis

Abstract Multiple myeloma is a lymphoproliferative disorder characterised by the clonal proliferation of plasma cells. Marrow interstitial fibrosis is common in myeloma. Data concerning the correlation of marrow fibrosis with clinical parameters and survival in patients with myeloma is conflicting. We have studied here the impact of marrow fibrosis at presentation in patients with myeloma on overall survival. This study included 38 (F: 22; M: 16) patients with myeloma from two teaching hospitals between May 1995 and March 2005. The diagnosis of myeloma is made on the basis of standard clinico-morphological criteria. At diagnosis patients underwent bone marrow aspiration and trephine biopsy along with routine haematological, biochemical and radiological investigations. Iliac crest biopsies were fixed in 4% formaldehyde, decalcified in EDTA and embedded in paraffin. Conventional staining for cellular components included haematoxylin and eosin (H& E). Reticulin silver impregnation staining is employed as standard matrix stain. H & E slides were reviewed by the histopathologist for degree and pattern of plasma cell infiltration. Reticulin staining was initially independently assessed by three of the authors, which was subsequently blindly confirmed by the haematopathologists. Bone marrow reticulin is quantified as Grade 0 when no reticulin fibres, Grade 1occasional fine individual fibres, Grade 2 fine fibre network, Grade 3 diffuse fibre network with scattered coarse fibres and grade 4 diffuse coarse fibre network. Patients received either intensive or non intensive anti-myeloma therapy as per standard practise. Median age at diagnosis was 65.3yrs (Range: 39–86 yrs) and the median follow up period was 16 months (Range: 0–121months). Para protein types were IgG: 23; IgA: 7; LC: 6; IgD: 1 & IgM: 1. 20 patients received VAD chemotherapy, 6 patients had Melphalan therapy, 5 patients were not given any therapy, 3 patients received oral Cyclophosphamide and 2 patients each received steroids and thalidomide alone as initial therapy. Bone marrow reticulin was increased in 25 patients and normal in 13 patients. Haemoglobin <8gms/dl was observed in 8 (24%) patients. 23 (74%) patients were positive for Bence-Jones protein. 17 (47%) patients had elevated serum calcium. 12(57%) patients had a β2-microglobulin of >4mg/ L and 6(16%) patients had renal failure. 21 patients required single line of therapy, where as 12 patients needed more than one line of therapy. Bone marrow reticulin, sex of the patient, presence of Bence-Jones protein, presence of renal failure at diagnosis did not impact on the overall survival(P values: 0.9, 0.8, 0.9 & 0.6 respectively), where as Hb< 8gm/ dl, hypercalcemia and elevated β2-microglobulin at diagnosis was associated with poor overall survival(P values: <0.0001, 0.2 & 0.04 respectively). Bone marrow reticulin also had no effect on the requirement for more than one line of therapy (P value: 0.7). Multivariate analysis revealed only Hb<8gm/dl as the independent predictor of poor overall survival (P Value: 0.03). Bone marrow fibrosis at diagnosis does not impact on the overall survival in patients with myeloma. Marrow fibrosis also doesn’t predict the need for more than one line of therapy in patients with myeloma. Our study also confirms the poor prognostic role of anaemia, hypercalcemia and elevated β2-microglobulin levels in patients with myeloma. Further studies are needed to confirm these and also the impact of anti-myeloma therapy on the marrow fibrosis.

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Racial Disparities in Incidence and Survival for Patients with Multiple Myeloma in the United States

Blood ◽

10.1182/blood.v126.23.4508.4508 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4508-4508

Author(s):

Lakshmi Radhakrishnan ◽

Sagar Lonial ◽

Ajay K. Nooka

Keyword(s):

Overall Survival ◽

Black Males ◽

Research Funding ◽

The United States ◽

Incidence Rates ◽

P Value ◽

Independent Factor ◽

Black Race ◽

Black Patients ◽

Adjusted Incidence

Abstract Background: Over the past two decades the incidence of myeloma has been gradually increasing in the United States. The incidence rates are higher in men than women, and higher in blacks than whites. Similar to the differential incidence, overall survival rate between blacks and whites are also dissimilar; a difference that is not completely explained and may be attributable to genetic variations between the two groups. Methods: Using data from 18 SEER registries, we examined differences in incidence, mortality and survival from 1973-2012 for 89,867 myeloma patients (68,701 white, 16,364 black and 4,802 others) by race, gender and age-stratification. ICD-O-3 and morphologic (9732/3) codes were used to identify cases. Age-adjusted incidence and mortality rates, regression analysis and survival curves were calculated by race. Statistics were computed using the National Cancer Institute SEER*Stat software, version 8.2.0. and SAS software, version 9.4 (SAS Institute Inc, Cary, NC). Results: Median age at diagnosis was 70 years (range 20-100 years) for the overall population (blacks: 66 years; whites: 71 years, and others: 69 years (P<0.01). The age-adjusted incidence rates per 100,000 populations were: blacks- 11.9 (95% CI 11.6, 12.1, P-value<0.05); whites- 5.1 (95% CI 5.0, 5.2) and others- 3.7 (95% CI 3.6, 3.9). The incidence rates were higher for black males, 14.2 (95% CI 14, 14.7) followed by black females, 10.3 (95% CI 10, 10.6, P-value<0.05). Using white male as reference, incidence rate ratios for black males and females are 2.20 (95% CI 2.12, 2.28) and 1.60 (95% CI 1.54, 1.65) respectively. The 2-year relative survival rates (RSR) for the study population were: whites- 60.4%, blacks: 64.1% and others: 68.4%, respectively. The 5-year RSR by race and gender are included in figure 1. On the survival analysis, black race is an independent factor to have improved survival (HR=0.884, P-value<0.0001). This was corroborated on regression analysis, showing decreased hazard ratios for blacks (HR 0.856 95% CI 0.834, 0.878) compared to whites (P-value<0.001). Conclusions: Black patients are diagnosed younger than whites and other races. The IRRs for black males are twice compared to white males. While the 5-year RSRs are improving for all races and genders, black race is an independent factor to have improved survival. Further population-based studies focused on the exploring the underlying biological mechanisms of disease may explain the earlier presentation with disease and better overall survival among black patients. Figure 1. Figure 1. Disclosures Lonial: Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Nooka:Onyx Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy.

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Ancestry-specific polygenic scores and SNP heritability of 25(OH)D in African- and European-ancestry populations

10.1101/596619 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kathryn E. Hatchell ◽

Qionshi Lu ◽

Scott J. Hebbring ◽

Erin D. Michos ◽

Alexis C. Wood ◽

...

Keyword(s):

Vitamin D ◽

Genetic Risk ◽

Genetic Factors ◽

African Ancestry ◽

The United States ◽

Vitamin D Supplementation ◽

European Ancestry ◽

P Value ◽

Vitamin D Intake ◽

Polygenic Scores

AbstractContextVitamin D inadequacy, assessed by 25-hydroxyvitamin D [25(OH)D], affects around 50% of adults in the United States and is associated with numerous adverse health outcomes. Blood 25(OH)D concentrations are influenced by genetic factors that may determine how much vitamin D intake is required to reach optimal 25(OH)D. Despite large genome-wide association studies (GWASs), only a small portion of the genetic factors contributing to differences in 25(OH)D levels has been discovered.ObjectiveTherefore, knowledge of a fuller set of genetic factors could be useful for risk prediction of 25(OH)D inadequacy, personalized vitamin D supplementation, and prevention of morbidity and mortality from deficient 25(OH)D.DesignUsing PRSice and weights from published African- and European-ancestry GWAS summary statistics, ancestry-specific polygenic scores (PGSs) were created to capture a more complete set of genetic factors.Patients or Other ParticipantsParticipants (European ancestry n=9,569, African ancestry n=2,761) came from three cohort studies.Main Outcome Measure(s)Blood concentrations of 25(OH)D.ResultsThe PGS for African ancestry was derived using all input SNPs (a p-value cut-off of 1.0) and had an R2of 0.3%; for European ancestry, the optimal PGS used a p-value cut-off of 3.5×10−4in the target/tuning dataset and had an R2of 1.0% in the validation cohort. Those with highest genetic risk had 25(OH)D that was 2.8-3.0 ng/ml lower than those with lowest genetic risk (p=0.0463 to 3.2×10−13), requiring an additional 467 to 500 IU of vitamin D intake to maintain equivalent 25(OH)D.ConclusionsPGSs are a powerful predictive tool that could be leveraged for personalized vitamin D supplementation to prevent the negative downstream effects of 25(OH)D inadequacy.

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Clinical Impact of Gastric Acid Suppressants Use on the Efficacy of Gefitinib in Patients with Advanced Adenocarcinoma of the Lung Harboring Common EGFR Mutations

Clinical Cancer Drugs ◽

10.2174/2212697x06666191021155535 ◽

2020 ◽

Vol 7 (1) ◽

pp. 57-61

Author(s):

Wang Chun Kwok ◽

James Chung Man Ho ◽

David Chi Leung Lam ◽

Macy Mei Sze Lui ◽

Mary Sau Man Ip ◽

...

Keyword(s):

Overall Survival ◽

Gastric Acid ◽

Proton Pump ◽

Progression Free Survival ◽

The United States ◽

Clinical Impact ◽

Egfr Mutations ◽

P Value ◽

First Line ◽

Free Survival

Background: Gefitinib was approved by the Food and Drug Administration (FDA) of the United States (US) for the treatment of advanced non-small cell carcinoma harboring sensitizing epidermal growth factor receptor (EGFR) mutations. The use of gastric acid-suppressing medication inhibits gefitinib absorption and reduces its plasma concentration, but retrospective studies on whether there is the corresponding repercussion on progression-free survival (PFS) have yielded variable results, mainly due to heterogeneity in study cohorts and study designs. Objectives: To assess the clinical impact of the use of gastric acid-suppressing medication in patients on first-line gefitinib for NSLC harboring common EGFR mutation. Methods: This is a retrospective cohort study conducted in a single, tertiary referral center in Hong Kong S.A.R., which included 193 Chinese patients with advanced adenocarcinoma of lung harboring common sensitizing EGFR mutations who received gefitinib as the first-line treatment. The progression- free survival (PFS) and overall survival (OS) for patients who took gastric acid-suppressing agents, namely histamine-2 receptor antagonists (H2RA) or proton pump inhibitors (PPI), were compared with those who did not take such medication (control group). Results: Despite the universal practice to separate the medicating time of gastric acid suppressants and EGFR-TKIs by 12 hours, patients who were on gastric acid suppressants had significantly shorter PFS, especially for those on proton pump inhibitor (Median 368 vs. 189 vs. 166 days - For control, H2RA group and PPI group respectively, p-value <0.001). The OS is also significantly shorter for those taking gastric acid suppressants (Median 825 vs. 485 vs. 422 days - For control, H2RA group and PPI group respectively, p-value <0.001). Conclusions: The co-administration of gastric acid suppressants with gefitinib is associated with shorter progression-free survival and overall survival.

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Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

10.1101/050195 ◽

2016 ◽

Author(s):

Andrea Ganna ◽

Giulio Genovese ◽

Daniel P. Howrigan ◽

Andrea Byrnes ◽

Mitja Kurki ◽

...

Keyword(s):

General Population ◽

Neurodevelopmental Disorders ◽

Cognitive Abilities ◽

Rare Variants ◽

De Novo ◽

Neurodevelopmental Disorder ◽

P Value ◽

Sequencing Data ◽

Whole Exome ◽

Number Variation

Ultra-rare inherited and de novo disruptive variants in highly constrained (HC) genes are enriched in neurodevelopmental disorders 1–5. However, their impact on cognition in the general population has not been explored. We hypothesize that disruptive and damaging ultra-rare variants (URVs) in HC genes not only confer risk to neurodevelopmental disorders, but also influence general cognitive abilities measured indirectly by years of education (YOE). We tested this hypothesis in 14,133 individuals with whole exome or genome sequencing data. The presence of one or more URVs was associated with a decrease in YOE (3.1 months less for each additional mutation; P-value=3.3×10−8) and the effect was stronger in HC genes enriched for brain expression (6.5 months less, P-value=3.4×10−5). The effect of these variants was more pronounced than the estimated effects of runs of homozygosity and pathogenic copy number variation 6–9. Our findings suggest that effects of URVs in HC genes are not confined to severe neurodevelopmental disorder, but influence the cognitive spectrum in the general population

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