Analysis of Shared Heritability in Common Disorders of the Brain

Anttila, Verneri; Bulik-Sullivan, Brendan; Finucane, Hilary; Brás, José; Duncan, Laramie; Escott‐Price, Valentina; Falcone, Guido J; Gormley, Padhraig; Malik, Rainer; Patsopoulos, Nikolaos A.; Ripke, Stephan; Walters, Raymond; Wei, Zhi; Yu, Dongmei; Lee, Phil; Metastroke,; Ocd,; Breen, Gerome; Bulik, Cynthia M.; Daly, Mark J.; Dichgans, Martin; Faraone, Stephen V.; Guerreiro, Rita; Holmans, Peter; Kendler, Kenneth S.; Koeleman, Bobby P. C.; Mathews, Carol A.; Scharf, Jeremiah M.; Sklar, Pamela; Williams, Julie; Wood, N. W.; Cotsapas, Chris; Palotie, Aarno; Smoller, Jordan W.; Sullivan, Patrick F.; Rosand, Jonathan; Corvin, Aiden; Neale, Benjamin M.

doi:10.1101/048991

Cited by 375 publications

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“…A recent large-scale cross-disorder study using GWAS summary statistics from 23 different neurologic and psychiatric disorders demonstrated that a significant proportion of GTS polygenic heritability is shared with OCD, ADHD and migraine 76 . While OCD and ADHD have long been known to share heritability with GTS 70 , the shared genetic relationship between migraine and GTS is novel.…”

Section: Shared Genetic Basis With Other Neuropsychiatric and Neurolomentioning

confidence: 99%

Gilles de la Tourette syndrome

Robertson

Eapen

Singer

et al. 2017

Nat Rev Dis Primers

296

244

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The unstructured abstract of 200 words maximum should summarize the main points of the article. All information mentioned in the abstract must be addressed somewhere in the main article. The abstract should not contain references or display item citations. Gilles de la Tourette Syndrome (GTS), a reasonably common disorder, has had a long, tortuous and somewhat controversial history. First and well described in the 18th century 1,2 , the main features of GTS have, however, remained fairly constant. The core diagnostic features are multiple motor and one or more vocal (phonic) tics lasting for over a year. In addition, almost pathognomic, but not necessary, features described in the early documentations include coprolalia (involuntary, inappropriate swearing), and echophenomena (copying behaviours), as well as many co-morbidities and psychopathologies 3 . Introduction [suggested 500 words, is 544 words -8 refs] Mary Robertson Thoughts for Mary -Your word count when combining sections 1 and 2 is 1001 (1000 limit)-so OKGTS was originally described in France and the majority of early literature came from and standardised schedules such as diagnostic confidence, measurement of severity, QoL, and assessment of both co-morbidities and co-existent psychopathologies are currently available.Large international collaborative consortia are engaged in studies exploring aetiological factors in particular, and some international treatment studies are also underway. Perhaps as a result of earlier small patient numbers, the treatment trials have given good clues to management, but unsurprisingly systematic reviews and meta-analyses have been hampered, giving disappointing, if not unexpected, results. Intriguingly medications from the typical NRDP -Gilles de la Tourette Syndrome 3 antipsychotic family including haloperidol, which first had documented success in 1961 6,7 are still being used, although successive generations of "atypicals" are currently more in vogue,as are medications such as alpha-2-adrenergic agonists. Interestingly, haloperidol remains the only medication prescribed on licence in many parts of the world. In contrast to disorders such as ADHD, in which it is clear which treatments work and which do not require further study 8 , a variety of treatment studies in GTS are still being undertaken, including using other medications (trying to improve efficacy and reduce side effects), behavioural therapies, deep brain stimulation (for refractory cases), and other more "alternative" methods such as "orthotics" (teeth braces). The GTS community has to first agree on how common GTS is and then seek funding for research in the areas of major importance.2. Epidemiology [suggested 500 words, is 444 words, 6 additional refs] Mary Robertson GTS was for many years thought to be not only very rare, but a bizarre curiosity, with sporadic case reports peppering the literature. The belief that GTS was uncommon at the very least was held by many until Comings 9 controversially suggested that GTS occurred in between 0.66% and...

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Section: Shared Genetic Basis With Other Neuropsychiatric and Neurolomentioning

confidence: 99%

Gilles de la Tourette syndrome

Robertson

Eapen

Singer

et al. 2017

Nat Rev Dis Primers

296

244

View full text Add to dashboard Cite

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“…[17], which gives the squared correlation between the true genetic effects of the SNPs, š , and ÊËÌÍ Î as: Eq. [39] is similar to Eq. [38] apart from the factor 1 − š 0 .…”

Section: Loss Of Prediction Accuracy When Approximating a Blup Predictormentioning

confidence: 91%

“…GREML SNP-heritability estimated for psychiatric disorders usually ranges from 15% to 30%, depending on the disease, and these estimates are roughly half of the estimates derived from family studies [10,19,39]. However, some studies estimate the SNP-heritability of Autism Spectrum Disorder to be between 50% -60% [40,41], while other studies give estimates ranging from 17% -24% [10,42].…”

Section: Examples Of Applications To Psychiatric Disordersmentioning

confidence: 99%

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The genetic architecture of psychiatric disorders

Maier¹

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The genetic nature of psychiatric disorders was observed by clinicians long before DNA had been identified as the molecule of inheritance. The greatest identified risk factor of many psychiatric disorders still is a positive family history. Until recently this knowledge has not contributed substantially to treatment efforts or to a better understanding of the disease processes because we lacked the necessary genetic data. Advances in genotyping technologies have brought an end to this data shortage which is leading to a better understanding of the genetic architecture of psychiatric disorders. Two patterns started to emerge which were uncommon in earlier studied Mendelian disorders. (i) most of the genetic part of disease risk is conferred by a large number of genetic loci of small effect, and (ii) genetic loci often influence a large number of traits at the same time. While this is true of many traits ("complex" traits), these two phenomena (polygenicity and pleiotropy) are particularly pronounced in psychiatric disorders. This has wide-reaching consequences for the analysis and interpretation of genetic data and provides challenges as well as opportunities. This thesis focuses on two areas in particular: genetic heterogeneity and genetic risk prediction.Genetic heterogeneity in a phenotypically homogenous group describes a situation where different and distinct genetic risk profiles are causing similar symptoms in different people.This can be easily identified under a Mendelian inheritance pattern, but proves to be challenging under polygenicity. The presence of genetic heterogeneity can limit the accuracy of genetic risk prediction.The aim of genetic risk prediction is to use the information that has been gathered on the effects of genetic loci to estimate the genetic liability of an individual to develop a disease.Here, pleiotropy offers an opportunity to increase the accuracy of genetic prediction by leveraging information from multiple diseases at the same time.The aim in this thesis is to describe several projects which center around the two concepts of genetic risk prediction based on multiple traits and of genetic heterogeneity. Chapter 1 sets the scene with an overview of recently developed polygenic methods. Chapter 2 deals with the effects of genetic heterogeneity on heritability estimates and demonstrates how genetic heterogeneity might contribute to the phenomenon of missing heritability, which is 3 the discrepancy between twin study heritability estimates and the variance explained by the sum of individual genetic loci. Chapter 3 addresses the question of whether genotype clustering can detect groups with different genetic risk profiles. Chapter 4 describes the implementation of a multivariate extension to the univariate Best Linear Unbiased Prediction (BLUP) method and its application to five psychiatric traits. Chapters 4 and 5 investigate whether this multivariate BLUP model can be approximated when only summary statistics, not individual level genotype data, are available for the predi...

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“…However, recent methodological developments using GWAS (raw) data [47] or summary statistics [48,49] have reported widespread genetic correlations between MDD and psychiatric traits (ADHD, BD, SCZ) [10,11,613], as well as with migraine or educational attainment [613].…”

Section: Comorbidities Of Depressionmentioning

confidence: 99%

Breaking down the genetics of depression using brain endophenotypes

Couvy‐Duchesne¹

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The Queensland Brain Institute 2 Thesis AbstractThe objective of the work presented in this thesis was to extend our understanding of depression aetiology and to identify brain MRI endophenotypes of depression. Our work builds on previous research that highlighted the genetic relationships between stress, sex and depression. In addition, MRI measurements are heritable and do not relying on selfreport. As such, they represent promising endophenotypes that could help break down further the genetics of depression.Preliminary work involved reporting depression prevalence in a young adult Australian twin sample (N=2,773) as well as comorbidity with affective and substance use disorders (Chapter 1). In addition, we demonstrated the good psychometric properties of the SPHERE questionnaire, which provides self-reported measures of anxiety-depression and chronic fatigue. Properties of the scores include: i) stochastic ordering on the sum score, ii) limited sex and age bias through adolescence, iii) high internal consistency, iv) good 3 months test-retest, v) moderate heritability, vi) significant association with lifetime MDD, social anxiety and alcohol dependence diagnoses (Chapter 2).In an older sample of Australian twins (N=5,221, Chapter 3), we performed a direct test of the diathesis-stress hypothesis in depression, which states that stressors can mediate the effect of genetic predisposition (diathesis) on the disease risk. We used Polygenic Risk Scores as a measure of diathesis and report a significant interaction with personal stressful life events, supporting the idea that stress and predisposition have a multiplicative effect on the depression liability scale. This interaction may be different between sexes as suggested by the stratified analysis.We then performed 3 analyses of resting-state fMRI from which we showed that: 1) Head motion (HM) is reliable and heritable in addition to being a major confound in fMRI analyses. However, this is unlikely to greatly confound twin studies of resting-state functional connectivity (FC). As a by-product of the analysis we showed that FC in the Broca's areas networks exhibited low to moderate test-retest and heritability (Chapter 4).2) HM is phenotypically and genetically associated with ADHD scores of Inattention and Hyperactivity/Impulsivity. This leads to most head motion image processing options to reduce power and/or to induce a sampling bias in RS-fMRI studies of ADHD. We discussed ways of circumventing this problem, via volume pruning or multivariate analysis (Chapter 5). 33) Nuisance regression (global signal regression, CompCor and HM regression) options in RS-fMRI processing have a moderate impact on the test-retest of regional homogeneity. Independently of the processing options, the low to moderate intra-class coefficients estimated in our sample may be due to insufficient scanning time (5mins 20s) and would impair our statistical power to detect RS-fMRI endophenotypes of depression (Chapter 6).Rather, we focused on structural brain images and contributed sample...

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Analysis of Shared Heritability in Common Disorders of the Brain

Abstract: on behalf of the Brainstorm consortium 1 7 2 4 UK 2 5

Cited by 375 publications

References 79 publications

Gilles de la Tourette syndrome

Gilles de la Tourette syndrome

The genetic architecture of psychiatric disorders

Breaking down the genetics of depression using brain endophenotypes

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