- Email: [email protected]
MITOCHONDRIAL DNA HAPLOGROUPS ARE ASSOCIATED WITH PSYCHIATRIC DISEASE: A NATION-WIDE STUDY OF 74,763 DANES
EXOME-WIDE ASSOCIATION STUDY IDENTIFIES NOVEL SUSCEPTIBILITY GENES FOR PERSONALITY TRAITS molecular mechanisms for ASD with relevant context and details. Note we have the full manuscript including all figures, tables and supplementary data posted online at http:// biorxiv.org/content/early/2016/05/11/052878.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.012
12. GENOME-WIDE ASSOCIATION META-ANALYSIS IDENTIFIES NEW LOCI AND GENES INFLUENCING HUMAN INTELLIGENCE
Suzanne Sniekers1, Sven Stringer1, Kyoko Watanabe1, Cornelia van Duijn2, Philip Jansen1, Gerome Breen3, Henning Tiemeier2, Robert Plomin3, Anthony Payton4, Neil Pendleton4, Jeanne Savage1, n Danielle Posthuma ,1 1
VU Amsterdam Erasmus MC 3 King's College London 4 University of Manchester 2
S787
(rg=0.89, LD Score regression P=5.4 10–29). SNP-based heritability was estimated at 0.20 (SE=0.01) in the total sample, and this was comparable in adults (0.21, SE=0.01) and children (0.20; SE=0.03). Bivariate LD score regression analysis shows positive genetic correlations with a.o.smoking cessation, and autism spectrum disorder, and negative genetic correlations with Alzheimer's disease, depressive symptoms, schizophrenia, and neuroticism. Discussion: Of all 52 genes that were implicated, 35 were reported in the GWAS catalog for a previous association with at least one of 67 distinct traits. Nine genes (ATP2A1, NEGR1, SKAP1, FOXO3, COL16A1, YIPF7, DCC, SH2B1 and TUFM) were previously implicated with body mass index, seven (CYP2D6, NAGA, NDUFA6, TCF20 and SEPT3, FAM109B and MEF2C) with schizophrenia0 and four (NEGR1, SH2B1, DCC and WNT4) with obesity. EXOC4 and MEF2C have been associated previously with Alzheimer's disease. This is the largest GWAS for intelligence so far and for the first time shows multiple robust associations for intelligence, suggesting several functional mechanisms, such as neuronal development and regulation of cell death. These findings provide novel insight into the genetic architecture of intelligence, which may also be important to various psychiatric traits such as schizophrenia and autism spectrum disorder.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.013
Background: Intelligence is associated with important economic and health-related life outcomes. Despite substantial heritability (0.54) and confirmed polygenic nature, initial genetic studies were mostly underpowered. We recently conducted a meta-analysis for intelligence of 78,308 individuals, and report 18 genomic loci, of which 15 are novel and 52 genes, of which 40 are novel. We expect to have increased this sample size further by October 2017. Methods: The combined data currently available data yielded GWAS information for intelligence for 78,308 unrelated individuals from 13 cohorts. All association studies were performed on individuals of European descent; standard quality-control procedures included correcting for population stratification and filtering on minor allele frequency and imputation quality. As eight out of the 13 cohorts consisted of children (aged o 18; total N =19,509) and five of adults (N = 58,799, aged 18–78), we first metaanalyzed the children- and adult-based cohorts separately using METAL software, and subsequently calculated the rg using LD Score regression. We used the results of an earlier GWAS for education attainment for proxy replication. Results: We identify 336 single nucleotide polymorphisms (SNPs) (METAL Po5 10-8) in 18 genomic loci, of which 15 are novel. Roughly half are located inside a gene, implicating 22 genes, of which 11 are novel findings. Gene-based analyses identified an additional 30 genes (MAGMA Po2.73 10-6), of which all but one have not been implicated previously. We show that identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P=3.5 10-6). Despite the well-known difference in twinbased heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation
1:30 p.m. - 3:00 p.m. Saturday Afternoon Oral Session: Biostatistics 13. MITOCHONDRIAL DNA HAPLOGROUPS ARE ASSOCIATED WITH PSYCHIATRIC DISEASE: A NATION-WIDE STUDY OF 74,763 DANES n
Michael Christiansen ,1, Jonas Bybjerg-Grauholm1, Christian Hagen1, Vanessa Goncalves2, Marie Bækvad-Hansen1, Christine Hansen1, Paula Hedley1, Ole Mors3, Thomas Als3, James Kennedy2, Merete Nordentoft4, Anders Børglum3, Preben Bo Mortensen3, Thomas Werge4, David Hougaard1 1
Statens Serum Institut University of Toronto 3 Aarhus University 4 Capital Region of Denmark 2
Background: Disturbed mitochondrial function has been implicated in psychiatric disease. All mitochondria contain a small maternally inherited DNA (mtDNA) of 16.6 kb. Through evolution and genetic drift, the mtDNA sequence has become fixed into haplogroups (hgs) with a characteristic population and geographical distribution. Different hgs exhibit variable functional capacity and have been demonstrated to be susceptibility factors for various, predominantly degenerative,
S788 diseases. Associations with Parkinsons and Alzheimers diseases, as well as cardiac, metabolic and psychiatric disorders have been reported. These findings have prompted the suggestion that variations in mitochondrial function might be susceptibility factors for disease. However, reports on association between mtDNA hgs and disease have frequently been conflicting. This is partly due to population stratification in examined populations and low-powered study designs. We analysed the association between mtDNA hgs and psychiatric disease using a very large geographically unbiased cohort, iPSYCH, comprising 2% of Danes as controls and 50,000+ psychiatric patients. Methods: Using DNA extracted from dried blood spots from 50,567 Danish psychiatric patients (ADHD: 13,103; ASD: 12,891; Anorexia: 2,124; BD: 1,242; SCZ: 2,438, and AD: 16,225) and 24,196 controls we examined the association between psychiatric disease and mtDNA haplogroup in the Danish population. Psychiatric patients were identified from the Danish Psychiatric Central Registry. DNA was obtained from the Danish Neonatal Screening Biobank. Haplotyping was performed using the PGC developed PsychChip v.1.0. containing 418 SNPs in mtDNA. The SNP data were manually analysed and haplotyped according to haplogroup defining SNPs in Phylotree. Results: Hg M was associated with affective disorder (n = 17260) with an OR of 0.47 (cfi.95%: 0.39 – 0.58) (p = 1n10– 14), ADHD (n = 13395) with an OR of 0.50 (0.40 – 0.62)(p = 2n10–11). Among patients belonging to the macro-hg N, patients with schizophrenia (n = 2589), had a high proportion of hg A (n = 45), OR: 4.52 (cfi.95%: 3.0 – 6.7)(p = 1.2n10–12). No significant associations between mtDNA hgs and BD or ASD were found. In a mitoGWAS for all six conditions, three mitoSNPs were highly associated with affective disorder (p-values ranging from 2n10E-25 – 2n10E-21), ADHD (p-values: 2n10E-11 – 1n10E-10), and anorexia (p-values: 6n10E -8 - 6n10E-7) and another mitoSNP with schizophrenia (p = 2n10–11). Discussion: Psychiatric disease seems to be bigenomic diseases with contributions from both the mitochondrial and nuclear genome. Haplogroup A is a risk factor for schizophrenia and haplogroup M is a protective factor for ADHD and affective disorder. However, both hgs A and M are infrequent in the Danish population and markers of Greenlandic and Asian origin, respectively. So it will be important through studies of interaction between mtDNA and the genomic DNA to precisely define the role of each of these factors in the etiology of psychiatric disease.
Disclosure: Nothing to disclose.
Y. Ma, M. Li
14. POLYGENIC RISK SCORES APPLIED TO UK BIOBANK DATA HIGHLIGHT THE INTERPLAY BETWEEN BEHAVIOUR AND PSYCHIATRIC DISORDERS n
Paul O'Reilly , Jessye Maxwell King's College London Background: Polygenic risk scores (PRS) are commonly used to infer shared genetic aetiology across phenotypes. Methods: Here we construct PRS for autism and schizophrenia and test their relationship with 17 behavioural and mood-related traits in the UK Biobank (N = 135 726). We also gain insights into the effects of disease onset and medication by contrasting the trends of behaviour observed with increasing genetic load in healthy individuals to that of medicated and non-medicated diagnosed individuals. Results: Genetic burden for autism and schizophrenia in the healthy population is associated with numerous behavioural and mood-related traits, including positive correlations between autism PRS and educational attainment (P = 2 10–20) and cognition (P = 1 10-7), and schizophrenia PRS and risk-taking (P = 4 10–26). Discussion: Self-reported risk-taking is associated with UK-based migration in terms of distance-moved (P = 2e-67) and increasing population density (P = 4e-73), and thus part of schizophrenia aetiology may be the genetics of risktaking, leading to migration, urbanicity or drug-taking – known risk factors for schizophrenia. This would be an example of an effect of genetics on a psychiatric disorder mediated by behaviour. Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.015
15. EFFECTS OF ASSORTATIVE MATING ON ESTIMATES OF SNP HERITABILITY n
Matthew Keller ,1, Teresa de Candia1, Matt Jones1, Rasool Tahmasbi1, Luke Evans1, David Evans2, Lindon Eaves3, Jian Yang2, Peter Visscher2, Mike Goddard4 1
http://dx.doi.org/10.1016/j.euroneuro.2017.08.014
2
University of Colorado, Boulder University of Queensland
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.012
12. GENOME-WIDE ASSOCIATION META-ANALYSIS IDENTIFIES NEW LOCI AND GENES INFLUENCING HUMAN INTELLIGENCE
Suzanne Sniekers1, Sven Stringer1, Kyoko Watanabe1, Cornelia van Duijn2, Philip Jansen1, Gerome Breen3, Henning Tiemeier2, Robert Plomin3, Anthony Payton4, Neil Pendleton4, Jeanne Savage1, n Danielle Posthuma ,1 1
VU Amsterdam Erasmus MC 3 King's College London 4 University of Manchester 2
S787
(rg=0.89, LD Score regression P=5.4 10–29). SNP-based heritability was estimated at 0.20 (SE=0.01) in the total sample, and this was comparable in adults (0.21, SE=0.01) and children (0.20; SE=0.03). Bivariate LD score regression analysis shows positive genetic correlations with a.o.smoking cessation, and autism spectrum disorder, and negative genetic correlations with Alzheimer's disease, depressive symptoms, schizophrenia, and neuroticism. Discussion: Of all 52 genes that were implicated, 35 were reported in the GWAS catalog for a previous association with at least one of 67 distinct traits. Nine genes (ATP2A1, NEGR1, SKAP1, FOXO3, COL16A1, YIPF7, DCC, SH2B1 and TUFM) were previously implicated with body mass index, seven (CYP2D6, NAGA, NDUFA6, TCF20 and SEPT3, FAM109B and MEF2C) with schizophrenia0 and four (NEGR1, SH2B1, DCC and WNT4) with obesity. EXOC4 and MEF2C have been associated previously with Alzheimer's disease. This is the largest GWAS for intelligence so far and for the first time shows multiple robust associations for intelligence, suggesting several functional mechanisms, such as neuronal development and regulation of cell death. These findings provide novel insight into the genetic architecture of intelligence, which may also be important to various psychiatric traits such as schizophrenia and autism spectrum disorder.
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.013
Background: Intelligence is associated with important economic and health-related life outcomes. Despite substantial heritability (0.54) and confirmed polygenic nature, initial genetic studies were mostly underpowered. We recently conducted a meta-analysis for intelligence of 78,308 individuals, and report 18 genomic loci, of which 15 are novel and 52 genes, of which 40 are novel. We expect to have increased this sample size further by October 2017. Methods: The combined data currently available data yielded GWAS information for intelligence for 78,308 unrelated individuals from 13 cohorts. All association studies were performed on individuals of European descent; standard quality-control procedures included correcting for population stratification and filtering on minor allele frequency and imputation quality. As eight out of the 13 cohorts consisted of children (aged o 18; total N =19,509) and five of adults (N = 58,799, aged 18–78), we first metaanalyzed the children- and adult-based cohorts separately using METAL software, and subsequently calculated the rg using LD Score regression. We used the results of an earlier GWAS for education attainment for proxy replication. Results: We identify 336 single nucleotide polymorphisms (SNPs) (METAL Po5 10-8) in 18 genomic loci, of which 15 are novel. Roughly half are located inside a gene, implicating 22 genes, of which 11 are novel findings. Gene-based analyses identified an additional 30 genes (MAGMA Po2.73 10-6), of which all but one have not been implicated previously. We show that identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P=3.5 10-6). Despite the well-known difference in twinbased heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation
1:30 p.m. - 3:00 p.m. Saturday Afternoon Oral Session: Biostatistics 13. MITOCHONDRIAL DNA HAPLOGROUPS ARE ASSOCIATED WITH PSYCHIATRIC DISEASE: A NATION-WIDE STUDY OF 74,763 DANES n
Michael Christiansen ,1, Jonas Bybjerg-Grauholm1, Christian Hagen1, Vanessa Goncalves2, Marie Bækvad-Hansen1, Christine Hansen1, Paula Hedley1, Ole Mors3, Thomas Als3, James Kennedy2, Merete Nordentoft4, Anders Børglum3, Preben Bo Mortensen3, Thomas Werge4, David Hougaard1 1
Statens Serum Institut University of Toronto 3 Aarhus University 4 Capital Region of Denmark 2
Background: Disturbed mitochondrial function has been implicated in psychiatric disease. All mitochondria contain a small maternally inherited DNA (mtDNA) of 16.6 kb. Through evolution and genetic drift, the mtDNA sequence has become fixed into haplogroups (hgs) with a characteristic population and geographical distribution. Different hgs exhibit variable functional capacity and have been demonstrated to be susceptibility factors for various, predominantly degenerative,
S788 diseases. Associations with Parkinsons and Alzheimers diseases, as well as cardiac, metabolic and psychiatric disorders have been reported. These findings have prompted the suggestion that variations in mitochondrial function might be susceptibility factors for disease. However, reports on association between mtDNA hgs and disease have frequently been conflicting. This is partly due to population stratification in examined populations and low-powered study designs. We analysed the association between mtDNA hgs and psychiatric disease using a very large geographically unbiased cohort, iPSYCH, comprising 2% of Danes as controls and 50,000+ psychiatric patients. Methods: Using DNA extracted from dried blood spots from 50,567 Danish psychiatric patients (ADHD: 13,103; ASD: 12,891; Anorexia: 2,124; BD: 1,242; SCZ: 2,438, and AD: 16,225) and 24,196 controls we examined the association between psychiatric disease and mtDNA haplogroup in the Danish population. Psychiatric patients were identified from the Danish Psychiatric Central Registry. DNA was obtained from the Danish Neonatal Screening Biobank. Haplotyping was performed using the PGC developed PsychChip v.1.0. containing 418 SNPs in mtDNA. The SNP data were manually analysed and haplotyped according to haplogroup defining SNPs in Phylotree. Results: Hg M was associated with affective disorder (n = 17260) with an OR of 0.47 (cfi.95%: 0.39 – 0.58) (p = 1n10– 14), ADHD (n = 13395) with an OR of 0.50 (0.40 – 0.62)(p = 2n10–11). Among patients belonging to the macro-hg N, patients with schizophrenia (n = 2589), had a high proportion of hg A (n = 45), OR: 4.52 (cfi.95%: 3.0 – 6.7)(p = 1.2n10–12). No significant associations between mtDNA hgs and BD or ASD were found. In a mitoGWAS for all six conditions, three mitoSNPs were highly associated with affective disorder (p-values ranging from 2n10E-25 – 2n10E-21), ADHD (p-values: 2n10E-11 – 1n10E-10), and anorexia (p-values: 6n10E -8 - 6n10E-7) and another mitoSNP with schizophrenia (p = 2n10–11). Discussion: Psychiatric disease seems to be bigenomic diseases with contributions from both the mitochondrial and nuclear genome. Haplogroup A is a risk factor for schizophrenia and haplogroup M is a protective factor for ADHD and affective disorder. However, both hgs A and M are infrequent in the Danish population and markers of Greenlandic and Asian origin, respectively. So it will be important through studies of interaction between mtDNA and the genomic DNA to precisely define the role of each of these factors in the etiology of psychiatric disease.
Disclosure: Nothing to disclose.
Y. Ma, M. Li
14. POLYGENIC RISK SCORES APPLIED TO UK BIOBANK DATA HIGHLIGHT THE INTERPLAY BETWEEN BEHAVIOUR AND PSYCHIATRIC DISORDERS n
Paul O'Reilly , Jessye Maxwell King's College London Background: Polygenic risk scores (PRS) are commonly used to infer shared genetic aetiology across phenotypes. Methods: Here we construct PRS for autism and schizophrenia and test their relationship with 17 behavioural and mood-related traits in the UK Biobank (N = 135 726). We also gain insights into the effects of disease onset and medication by contrasting the trends of behaviour observed with increasing genetic load in healthy individuals to that of medicated and non-medicated diagnosed individuals. Results: Genetic burden for autism and schizophrenia in the healthy population is associated with numerous behavioural and mood-related traits, including positive correlations between autism PRS and educational attainment (P = 2 10–20) and cognition (P = 1 10-7), and schizophrenia PRS and risk-taking (P = 4 10–26). Discussion: Self-reported risk-taking is associated with UK-based migration in terms of distance-moved (P = 2e-67) and increasing population density (P = 4e-73), and thus part of schizophrenia aetiology may be the genetics of risktaking, leading to migration, urbanicity or drug-taking – known risk factors for schizophrenia. This would be an example of an effect of genetics on a psychiatric disorder mediated by behaviour. Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.015
15. EFFECTS OF ASSORTATIVE MATING ON ESTIMATES OF SNP HERITABILITY n
Matthew Keller ,1, Teresa de Candia1, Matt Jones1, Rasool Tahmasbi1, Luke Evans1, David Evans2, Lindon Eaves3, Jian Yang2, Peter Visscher2, Mike Goddard4 1
http://dx.doi.org/10.1016/j.euroneuro.2017.08.014
2
University of Colorado, Boulder University of Queensland