Analysis of shared heritability

SEMINAR

María Jesús Grueso Alcántara

Analysis of shared heritabiLity IN COMMON DISORDERS OF THE BRAIN

Supervisor: Eva BeinsLife & Brain Universität Bonn

Neurogenetics

3. Results

5. References

2. Study design

4. Main conclusions

1. Introduction

TABLE OF CONTENTS

Brain disorders, overlaps among them and goals of the study

1. INTRODUCTION

...same as a good diagnosis.

Define Mondays

How do hugs feel?

'A picture is worth a thousand words'

NEUROLOGICAL DISORDERS

PSYCHIATRIC DISORDERS

Understanding the genetic underpinnings may inform about their biological mechanisms

What about its CLASSIFICATION? It has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena.

more overlaps or differences at the genomic level?

There are phenotypic and symptomatic overlaps, as well as shared individual common risk variants.

Brain disorders

Brain disorders included in the Brainstorm project

Linkage disequilibrium score (ldsc) regression

Heritability methods

Relation with brain disorders

Studies of twins and families have indicated that, in general, brain disorders (except those caused by trauma, infection or cancer) show substantial heritability.

HERITABILITY

Heritability is a statistic representing the percentage of phenotype variability that can be attributed to genetic variation.

dEFINITION

Inform the search for the biological mechanisms of brain disorders

Shed light on the nature of diagnostic boundaries in brain disorders

2. Explore how statistical power, diagnostic misclassification and phenotypic heterogeneity affect genetic correlations

1. Quantify the overlap for genetic risk factors of 25 brain disorders using GWAS data

MAIN GOALS OF THE STUDY

GWAS metaanalysis consortia for 25 disorders

2. STUDY DESIGN

STUDY SAMPLE

• 265218 patients with 25 different brain disorders.
• 784643 control participants.
• 1191588 individuals with 17 different phenotypes.

brainstorm consortium

GWAS meta-analyses of sufficient size for heritability analysis.

which meta-analysis were included?

Heritability estimates, error sources and correlations

3. RESULTS

Similar range of heritability estimates among the disorders and the behavioral-cognitive phenotypes.

3.1 heritability estimates and their error sources

are Methodological differences contributing to the variations in the estimates?

what about rare variants?

Early onset brain disorders tend to be more heritable

• Correlation between heritability and age of disorder onset.

SOME ATTENUATION IN HERITABILITY IS OBSERVED WHEN MOVING TO LARGER SAMPLE SIZES

3.1 heritability estimates and their error sources

• Common variant heritability estimates for the brain disorders were generally LOWER than previously reported estimates

3.2 correlations among brain disorders

Psychiatric disorders

Psychiatric disorders

Behavioural-cognitive and additional phenotypes

Psychiatric disorders

Behavioural-cognitive and additional phenotypes

Neurological disorders

Neurological disorders

Neurological disorders

Neurological disorders

Psychiatric disorders

3.2.1 widespread sharing across psychiatric disorders

1. Schizophrenia: significant genetic correlation with most of the psychiatric disorders.2. Significant sharing among: - Anorexia nervosa, OCD and schizophrenia. - TS, OCD and MDD.3. ASD and TS: potentially more distinct from the other psychiatric disorders. 4. PSTD: no significant correlation with any of the other psychiatric phenotypes.

3.2.2 Less sharing across neurological disorders

Suggesting greater diagnostic specifity and/or more distinct etiologies

1. Parkinson’s disease, AD, generalized epilepsy, and MS: little to no correlation with other brain disorders. 2. Focal epilepsy: highest degree of genetic correlation among the neurological disorders , though none of the correlations were significant.

Suggesting that migraine share some of its genetics with psychiatric disorders

3.2.3 LIMITED sharing across neurological AND PSYCHIATRIC disorders

1. The only significant cross-category correlations were with migraine.

BEHAVIOURAL-COGNITIVE PHENOTYPES

1. Years of education and college attainment: positive correlation with psychiatric disorders, negative correlation with neurological phenotypes.2. Neuroticism: correlated with almost every psychiatric disorder and migraine.

3.2.4 SIGNIFICANT CORRELATIONS BETWEEN phenotypes AND brain DISORDERS

3.2.5 SIGNIFICANT CORRELATIONS BETWEEN PHENOTYPES AND brain DISORDERS

ADDITIONAL PHENOTYPES

1. BMI: positively correlated with ADHD and MDD, and negatively correlated with anorexia nervosa.2. Myocardial infarction: correlation with MDD, ischemic stroke and early-onset stroke.

4. MAIN CONCLUSIONS

Psychiatric disorders share a considerable portion of their common variant genetic risk.Their current clinical boundaries do not reflect distinct underlying pathogenic processes.Neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine.Their current classification reflects relatively specific genetic etiologies.Neuroticism is significantly correlated with almost every psychiatric disorder and migraine.Years of education shows genetic sharing with different brain disorders, either positively or negatively.

take-home messages

1. Need to REFINE psychiatric nosology and diagnostics: genetically informed analyses may provide a basis, consistent with twin- and family-based results.2. The existing clinical delineation between neurology and psychiatry is corroborated at the level of common variant risk for the studied disorders.Multiple different and largely independently regulated etiological pathways may give rise to similar clinical manifestations. 3. Both psychiatric and neurological disorders show robust correlations with cognitive and personality measures, indicating avenues for follow-up studies.

outlook

6. references

Hill WG. Heritability. Brenner’s Encycl Genet Second Ed. 2013 Feb 27;432–4. Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J; Schizophrenia Working Group of the Psychiatric Genomics Consortium, Patterson N, Daly MJ, Price AL, Neale BM. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015 Mar;47(3):291-5. doi: 10.1038/ng.3211.

Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, Duncan L, et al. Analysis of shared heritability in common disorders of the brain. Science (80- ). 2018;360(6395).

any questions?

Hope you liked it!!!

14.2k

THANK YOU