- Email: [email protected]
CHROMOSOME X-WIDE ASSOCIATION STUDY IDENTIFIES A NEW LOCUS FOR LATE-ONSET ALZHEIMER’S DISEASE ON XQ25
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Podium Presentations: Sunday, July 16, 2017
Detroit, MI, USA; 4Michigan State University, East Lansing, MI, USA. Contact e-mail: [email protected] Background: Neurocognitive disorders, including Alzheimer’s
Disease (AD), are major public health problems that disproportionately affect Latinos. Measures of neurocognitive function, such as reasoning, spatial ability, memory, verbal ability, and information processing speed, are correlated and heritable. However, few genes other than APOE have been reproducibly associated with neurocognitive measures in non-demented communitydwelling adults. Methods: We conducted a genome-wide association study (GWAS) of neurocognitive function in Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Measures of neurocognitive function included global mental status (Six-item Screener), verbal learning and memory (Spanish English Verbal Learning Test, SEVLT), executive function and expressive language (Word Fluency Test, WFT), and psychomotor speed (Digit Symbol Substitution Test, DSST). Genotypes were imputed to 1000 Genomes phase 3 reference panel. We estimated linear mixed models for each trait. Fixed effects included sex, age, recruitment center, individual sampling weights, and top five principal components accounting for ancestry. Random effects included pairwise empirical kinship coefficients accounting for familial relatedness, household membership, and membership in a census block group. We further adjusted for “genetic analysis group” to account for additional group-associated effects. A pvalue <5x10-8was considered genome-wide significant. Results: In total 7,369 Hispanic/Latino individuals (61% female; age: 5568 years) were included in the analysis. Common variants (minor allele frequency (MAF) >0.05) were associated with neurocognitive measures: A locus at chromosome 4p14 associated with SEVLT (MAF: 6.1%, p ¼ 3.7x10-8) and a locus at chromosome 3p14.1 associated with WFT (MAF: 18.6%, p ¼ 5.09 x10-10). Variants at 4p14 are located within the RBM47 gene, which encodes a RNA-binding protein implicated in RNA editing and critical for head formation during zebrafish embryogenesis. Variants at 3p14.1 lie 2KB upstream of the gene FRMD4B, a hub gene in the myelination network which has been implicated in late-onset AD. Additionally, several rare variants were also identified for each of the neurocognitive measures. Conclusions: We have performed the first GWAS of neurocognitive function among Hispanic/Latinos and identified several genetic variants associated with measures of neurocognitive function. Replication is underway in an independent Hispanic American sample. We are also investigating whether these findings are generalizable in other ancestries including European Americans and African Americans.
O1-03-04
Figure 1. Two novel X-linked loci reach genome-wide significance in the Northwestern European cohort. The solid red line indicates the threshold for genome-wide significance (P < 5 x 10-8), and the blue line represents the threshold for suggestive hits (P < 1 x 10-5).
onset AD. Methods: We performed an XWA mega-analysis by combining 12987 Northwestern Europeans (NWE) from thirteen independent datasets, followed by replication using a cohort of 531 Southeastern Europeans (SEE). All the subjects analyzed belong to datasets included in the Stage 1 subset of the Alzheimer’s Disease Genetics Consortium, which has been described in previous studies. The datasets were accessed via dbGAP and NIAGADS and independently quality controlled using X-chromosome specific procedures implemented in XWAS 1.1. X-chromosome imputation was performed using the Haplotype Reference Consortium r1.1. panel. XWA testing was carried out by logistic regression in males and females, separately, and the results were combined using the Stouffer’s method implemented in XWAS 1.1. Gene-based analysis was performed using VEGAS2 software. Results: In the XWA mega-analysis, we identified two novel loci reaching genome-wide significance threshold (rs112930037, near DCAF12L2, MAF¼0.20,
CHROMOSOME X-WIDE ASSOCIATION STUDY IDENTIFIES A NEW LOCUS FOR LATE-ONSET ALZHEIMER’S DISEASE ON XQ25
Valerio Napolioni1, Raiyan R. Khan2, Michael D. Greicius1, 1Stanford University, Stanford, CA, USA; 2Stanford University School of Medicine, Stanford, CA, USA. Contact e-mail: [email protected] Background: Despite the collective evidence pointing to a
possible role for X-linked genes, no association study has clearly addressed their contribution to Alzheimer’s Disease (AD) or AD-related biomarkers. We aim to perform the first comprehensive X chromosome-wide association study (XWAS) of late-
Figure 2. XWAS top hit rs112930037 is located near DCAF12L2. The solid diamond represents the top ranked SNP in the region, based on two-sided P values. Pairwise correlation (r2) between the top SNP and the other SNPs in the region is indicated by color.
Podium Presentations: Sunday, July 16, 2017
P¼1.8x10-10; rs147122766, in the premature ovarian failure critical region, MAF¼0.26, P¼1.5x10-9). The top XWAS-hit rs112930037, near DCAF12L2, was successfully replicated in the SEE cohort (P¼0.018). rs112930037 increases risk for LOAD in both males and in females (males OR¼1.216, P¼0.011; females OR¼1.314, P¼6.0x10-10). Gene-based analysis failed to reveal genes associated with LOAD. Conclusions: Our study reveals the existence of an X-linked locus for LOAD on Xq25 DCAF12L2, which is one of the only two known retrogenes on the X chromosome and widely expressed in the brain. The parent gene DCAF12, located on 9p13.3 (a frontotemporal dementia linkage region), encodes a WD repeat-containing protein that interacts with the COP9 signalosome. Recent studies reveal that members of the COP9 signalosome were associated with several neurological disorders, including AD. By interacting with its parent gene DCAF12L2 may influence COP9 signalosome activity, thereby playing a role in dendritic morphogenesis as previously described in the Drosophila literature. Further studies will address the functional impact of genetic variation at the Xq25 locus in influencing susceptibility to LOAD.
O1-03-05
ANNOTATION-STRATIFIED GENETIC CORRELATION ANALYSIS IDENTIFIES SHARED AND DISTINCT GENETIC ARCHITECTURE OF LATE-ONSET ALZHEIMER’S DISEASE AND AMYOTROPHIC LATERAL SCLEROSIS
Qiongshi Lu1, Shubhabrata Mukherjee2, Paul K. Crane2, Hongyu Zhao1, 1 Yale University, New Haven, CT, USA; 2University of Washington, Seattle, WA, USA. Contact e-mail: [email protected] Background: Despite success of large-scale genome-wide associa-
tion studies (GWASs), our understanding of neurodegenerative diseases’ genetic architecture is incomplete. Integrative analysis of GWAS data and systematic functional genome annotations has provided insights into the genetic basis of complex diseases. Here we introduce and apply a novel method to dissect shared genetic components between late-onset Alzheimer’s disease (LOAD) and amyotrophic lateral sclerosis (ALS). Methods: We developed a principled framework to estimate annotation-stratified genetic correlation using GWAS summary statistics. We jointly analyzed LOAD Stage-I GWAS summary statistics from the International Genomics of Alzheimer’s Project (IGAP; n¼54,162) and ALS summary statistics from MinE (n¼36,052) with several functional annotations. We provide an atlas of genetic correlations for LOAD, ALS, and 50 complex traits through integrative analysis of summary statistics from publicly available GWASs (ntotalw4.5 million). Results: We identified substantial genetic correlation between LOAD and ALS (correlation¼0.18; p-value¼2.0310-4). 82.6% of the total genetic covariance between LOAD and ALS is concentrated in the 32% of the genome predicted to be functional (p-value¼8.2310-5). 54.6% of the covariance can be explained by the most common SNPs as indicated by the highest quartile of minor allele frequencies (MAF; p-value¼0.005). Genetic covariance in the lowest MAF quartile is nearly negligible. Furthermore, the genetic covariance between LOAD and ALS is concentrated in immune-related DNA elements (p-value¼0.014) while the covariance in brain-related DNA elements is non-significant. LOAD and ALS showed distinct patterns of
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genetic correlation with other complex traits. We identified significant negative correlation between LOAD and cognitive traits including cognitive function (correlation¼-0.26; p-value¼1.0310-11) and education attainment (correlation¼-0.20; p-value¼3.4310-12). ALS is positively correlated with immune-related diseases including multiple sclerosis (correlation¼0.39; p-value¼4.6310-4) and celiac disease (correlation¼0.54; p-value¼0.002). Conclusions: Annotationstratified analysis identifies strong genetic correlation between LOAD and ALS in common SNPs and in the predicted functional genome. Substantial covariance in immune-related DNA elements hints at an immune-mediated pleiotropic effect between LOAD and ALS. Joint analysis of 50 complex traits suggests that LOAD is genetically correlated with cognitive traits while ALS may have an autoimmune genetic component. Our findings provide novel insights into both the shared and distinct genetic architecture of LOAD and ALS.
O1-03-06
IDENTIFICATION OF AN ITGA7 VARIANT ASSOCIATED WITH ALZHEIMER’S DISEASE AND MULTIPLE OTHER NEURODEGENERATIVE DISEASES
Raiyan R. Khan1, Valerio Napolioni1, Andre Altmann2, William W. Seeley3, Thomas J. Montine1, Giovanni Coppola4, Jason A. Chen5, Edward D. Plowey1, Divya Channappa1, Aaron D. Gitler1, Julien Couthouis1, Margaret E. Flanagan1, Michael D. Greicius1, 1Stanford University School of Medicine, Stanford, CA, USA; 2Translational Imaging Group, Centre for Medical Image Computing, University College London, London, United Kingdom; 3University of California, San Francisco, San Francisco, CA, USA; 4Semel Institute for Neuroscience and Behavior at UCLA, Los Angeles, CA, USA; 5Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: The genetic causes of mixed Alzheimer’s Disease
(AD) and Dementia with Lewy Bodies (DLB) pathology remain unclear. In the current study we searched for exonic variants contributing to dual pathology in younger patients. Methods: We analyzed whole exome sequencing data collected through Stanford University and the Alzheimer’s Disease Sequencing Project (ADSP). High impact (missense or nonsense) variants found in
Figure 1. Normalized FPKM values of the three ITGA7 transcript isoforms encoding rs76938420 are significantly higher in AD cases (n ¼ 82) than in controls (n ¼ 80).ITGA7 transcript expression values in post-mortem brain tissue were corrected for subject age at death, gender, RIN, source, and cell type markers. *** P < 0.001.
Podium Presentations: Sunday, July 16, 2017
Detroit, MI, USA; 4Michigan State University, East Lansing, MI, USA. Contact e-mail: [email protected] Background: Neurocognitive disorders, including Alzheimer’s
Disease (AD), are major public health problems that disproportionately affect Latinos. Measures of neurocognitive function, such as reasoning, spatial ability, memory, verbal ability, and information processing speed, are correlated and heritable. However, few genes other than APOE have been reproducibly associated with neurocognitive measures in non-demented communitydwelling adults. Methods: We conducted a genome-wide association study (GWAS) of neurocognitive function in Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Measures of neurocognitive function included global mental status (Six-item Screener), verbal learning and memory (Spanish English Verbal Learning Test, SEVLT), executive function and expressive language (Word Fluency Test, WFT), and psychomotor speed (Digit Symbol Substitution Test, DSST). Genotypes were imputed to 1000 Genomes phase 3 reference panel. We estimated linear mixed models for each trait. Fixed effects included sex, age, recruitment center, individual sampling weights, and top five principal components accounting for ancestry. Random effects included pairwise empirical kinship coefficients accounting for familial relatedness, household membership, and membership in a census block group. We further adjusted for “genetic analysis group” to account for additional group-associated effects. A pvalue <5x10-8was considered genome-wide significant. Results: In total 7,369 Hispanic/Latino individuals (61% female; age: 5568 years) were included in the analysis. Common variants (minor allele frequency (MAF) >0.05) were associated with neurocognitive measures: A locus at chromosome 4p14 associated with SEVLT (MAF: 6.1%, p ¼ 3.7x10-8) and a locus at chromosome 3p14.1 associated with WFT (MAF: 18.6%, p ¼ 5.09 x10-10). Variants at 4p14 are located within the RBM47 gene, which encodes a RNA-binding protein implicated in RNA editing and critical for head formation during zebrafish embryogenesis. Variants at 3p14.1 lie 2KB upstream of the gene FRMD4B, a hub gene in the myelination network which has been implicated in late-onset AD. Additionally, several rare variants were also identified for each of the neurocognitive measures. Conclusions: We have performed the first GWAS of neurocognitive function among Hispanic/Latinos and identified several genetic variants associated with measures of neurocognitive function. Replication is underway in an independent Hispanic American sample. We are also investigating whether these findings are generalizable in other ancestries including European Americans and African Americans.
O1-03-04
Figure 1. Two novel X-linked loci reach genome-wide significance in the Northwestern European cohort. The solid red line indicates the threshold for genome-wide significance (P < 5 x 10-8), and the blue line represents the threshold for suggestive hits (P < 1 x 10-5).
onset AD. Methods: We performed an XWA mega-analysis by combining 12987 Northwestern Europeans (NWE) from thirteen independent datasets, followed by replication using a cohort of 531 Southeastern Europeans (SEE). All the subjects analyzed belong to datasets included in the Stage 1 subset of the Alzheimer’s Disease Genetics Consortium, which has been described in previous studies. The datasets were accessed via dbGAP and NIAGADS and independently quality controlled using X-chromosome specific procedures implemented in XWAS 1.1. X-chromosome imputation was performed using the Haplotype Reference Consortium r1.1. panel. XWA testing was carried out by logistic regression in males and females, separately, and the results were combined using the Stouffer’s method implemented in XWAS 1.1. Gene-based analysis was performed using VEGAS2 software. Results: In the XWA mega-analysis, we identified two novel loci reaching genome-wide significance threshold (rs112930037, near DCAF12L2, MAF¼0.20,
CHROMOSOME X-WIDE ASSOCIATION STUDY IDENTIFIES A NEW LOCUS FOR LATE-ONSET ALZHEIMER’S DISEASE ON XQ25
Valerio Napolioni1, Raiyan R. Khan2, Michael D. Greicius1, 1Stanford University, Stanford, CA, USA; 2Stanford University School of Medicine, Stanford, CA, USA. Contact e-mail: [email protected] Background: Despite the collective evidence pointing to a
possible role for X-linked genes, no association study has clearly addressed their contribution to Alzheimer’s Disease (AD) or AD-related biomarkers. We aim to perform the first comprehensive X chromosome-wide association study (XWAS) of late-
Figure 2. XWAS top hit rs112930037 is located near DCAF12L2. The solid diamond represents the top ranked SNP in the region, based on two-sided P values. Pairwise correlation (r2) between the top SNP and the other SNPs in the region is indicated by color.
Podium Presentations: Sunday, July 16, 2017
P¼1.8x10-10; rs147122766, in the premature ovarian failure critical region, MAF¼0.26, P¼1.5x10-9). The top XWAS-hit rs112930037, near DCAF12L2, was successfully replicated in the SEE cohort (P¼0.018). rs112930037 increases risk for LOAD in both males and in females (males OR¼1.216, P¼0.011; females OR¼1.314, P¼6.0x10-10). Gene-based analysis failed to reveal genes associated with LOAD. Conclusions: Our study reveals the existence of an X-linked locus for LOAD on Xq25 DCAF12L2, which is one of the only two known retrogenes on the X chromosome and widely expressed in the brain. The parent gene DCAF12, located on 9p13.3 (a frontotemporal dementia linkage region), encodes a WD repeat-containing protein that interacts with the COP9 signalosome. Recent studies reveal that members of the COP9 signalosome were associated with several neurological disorders, including AD. By interacting with its parent gene DCAF12L2 may influence COP9 signalosome activity, thereby playing a role in dendritic morphogenesis as previously described in the Drosophila literature. Further studies will address the functional impact of genetic variation at the Xq25 locus in influencing susceptibility to LOAD.
O1-03-05
ANNOTATION-STRATIFIED GENETIC CORRELATION ANALYSIS IDENTIFIES SHARED AND DISTINCT GENETIC ARCHITECTURE OF LATE-ONSET ALZHEIMER’S DISEASE AND AMYOTROPHIC LATERAL SCLEROSIS
Qiongshi Lu1, Shubhabrata Mukherjee2, Paul K. Crane2, Hongyu Zhao1, 1 Yale University, New Haven, CT, USA; 2University of Washington, Seattle, WA, USA. Contact e-mail: [email protected] Background: Despite success of large-scale genome-wide associa-
tion studies (GWASs), our understanding of neurodegenerative diseases’ genetic architecture is incomplete. Integrative analysis of GWAS data and systematic functional genome annotations has provided insights into the genetic basis of complex diseases. Here we introduce and apply a novel method to dissect shared genetic components between late-onset Alzheimer’s disease (LOAD) and amyotrophic lateral sclerosis (ALS). Methods: We developed a principled framework to estimate annotation-stratified genetic correlation using GWAS summary statistics. We jointly analyzed LOAD Stage-I GWAS summary statistics from the International Genomics of Alzheimer’s Project (IGAP; n¼54,162) and ALS summary statistics from MinE (n¼36,052) with several functional annotations. We provide an atlas of genetic correlations for LOAD, ALS, and 50 complex traits through integrative analysis of summary statistics from publicly available GWASs (ntotalw4.5 million). Results: We identified substantial genetic correlation between LOAD and ALS (correlation¼0.18; p-value¼2.0310-4). 82.6% of the total genetic covariance between LOAD and ALS is concentrated in the 32% of the genome predicted to be functional (p-value¼8.2310-5). 54.6% of the covariance can be explained by the most common SNPs as indicated by the highest quartile of minor allele frequencies (MAF; p-value¼0.005). Genetic covariance in the lowest MAF quartile is nearly negligible. Furthermore, the genetic covariance between LOAD and ALS is concentrated in immune-related DNA elements (p-value¼0.014) while the covariance in brain-related DNA elements is non-significant. LOAD and ALS showed distinct patterns of
P193
genetic correlation with other complex traits. We identified significant negative correlation between LOAD and cognitive traits including cognitive function (correlation¼-0.26; p-value¼1.0310-11) and education attainment (correlation¼-0.20; p-value¼3.4310-12). ALS is positively correlated with immune-related diseases including multiple sclerosis (correlation¼0.39; p-value¼4.6310-4) and celiac disease (correlation¼0.54; p-value¼0.002). Conclusions: Annotationstratified analysis identifies strong genetic correlation between LOAD and ALS in common SNPs and in the predicted functional genome. Substantial covariance in immune-related DNA elements hints at an immune-mediated pleiotropic effect between LOAD and ALS. Joint analysis of 50 complex traits suggests that LOAD is genetically correlated with cognitive traits while ALS may have an autoimmune genetic component. Our findings provide novel insights into both the shared and distinct genetic architecture of LOAD and ALS.
O1-03-06
IDENTIFICATION OF AN ITGA7 VARIANT ASSOCIATED WITH ALZHEIMER’S DISEASE AND MULTIPLE OTHER NEURODEGENERATIVE DISEASES
Raiyan R. Khan1, Valerio Napolioni1, Andre Altmann2, William W. Seeley3, Thomas J. Montine1, Giovanni Coppola4, Jason A. Chen5, Edward D. Plowey1, Divya Channappa1, Aaron D. Gitler1, Julien Couthouis1, Margaret E. Flanagan1, Michael D. Greicius1, 1Stanford University School of Medicine, Stanford, CA, USA; 2Translational Imaging Group, Centre for Medical Image Computing, University College London, London, United Kingdom; 3University of California, San Francisco, San Francisco, CA, USA; 4Semel Institute for Neuroscience and Behavior at UCLA, Los Angeles, CA, USA; 5Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: The genetic causes of mixed Alzheimer’s Disease
(AD) and Dementia with Lewy Bodies (DLB) pathology remain unclear. In the current study we searched for exonic variants contributing to dual pathology in younger patients. Methods: We analyzed whole exome sequencing data collected through Stanford University and the Alzheimer’s Disease Sequencing Project (ADSP). High impact (missense or nonsense) variants found in
Figure 1. Normalized FPKM values of the three ITGA7 transcript isoforms encoding rs76938420 are significantly higher in AD cases (n ¼ 82) than in controls (n ¼ 80).ITGA7 transcript expression values in post-mortem brain tissue were corrected for subject age at death, gender, RIN, source, and cell type markers. *** P < 0.001.