Analysis of shared heritability

Analysis of shared heritabiLity IN COMMON DISORDERS OF THE BRAIN

María Jesús Grueso Alcántara

SEMINAR

Neurogenetics

Supervisor: Eva Beins

Life & Brain

Universität Bonn

TABLE OF CONTENTS

1. Introduction

4. Main conclusions

2. Study design

5. References

3. Results

1. INTRODUCTION

Brain disorders, overlaps among them and goals of the study

'A picture is worth a thousand words'

How do hugs feel?

Define

Mondays

...same as a good diagnosis.

Brain disorders

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

more overlaps or differences at the genomic level?

What about its CLASSIFICATION?

It has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena.

Understanding the genetic underpinnings may inform about their biological mechanisms

PSYCHIATRIC DISORDERS

NEUROLOGICAL DISORDERS

GWASs have demonstrated that individual common risk variants can overlap across traditional diagnostic boundaries: e.g. schizophrenia, MDD and bipolar disorder

Brain disorders included in the Brainstorm project

dEFINITION

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

HERITABILITY

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

Relation with brain disorders

Heritability methods

Linkage disequilibrium score (ldsc) regression

This is not the same as saying that this percentage of an individual phenotype is caused by genetics!!

GWASs have demonstrated that genetic variation contributes to the heritability of brain disorders: combination of many common variants (each with a small individual effect)

MAIN GOALS OF THE STUDY

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

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

Shed light on the nature of diagnostic boundaries in brain disorders

Inform the search for the biological mechanisms of brain disorders

2. STUDY DESIGN

GWAS metaanalysis consortia for 25 disorders

which meta-analysis were included?

GWAS meta-analyses of sufficient size for heritability analysis.

brainstorm consortium

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

STUDY SAMPLE

3. RESULTS

Heritability estimates, error sources and correlations

3.1 heritability estimates and their error sources

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

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

3.1 heritability estimates and their error sources

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

Correlation between heritability and age of disorder onset.

Early onset brain disorders tend to be more heritable

what about rare variants?

are Methodological differences contributing to the variations in the estimates?

Heritability estimates should be interpreted cautiously!!

Psychiatric disorders

Neurological disorders

Behavioural-cognitive and additional phenotypes

Psychiatric disorders

Behavioural-cognitive and additional phenotypes

Psychiatric disorders

3.2 correlations among brain 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.

3.2.1 widespread sharing across psychiatric disorders

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 greater diagnostic specifity and/or more distinct etiologies

3.2.2 Less sharing across neurological disorders

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

3.2.3 LIMITED sharing across neurological AND PSYCHIATRIC disorders

Suggesting that migraine share some of its genetics with psychiatric disorders

3.2.4 SIGNIFICANT CORRELATIONS BETWEEN phenotypes AND brain DISORDERS

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.

BEHAVIOURAL-COGNITIVE 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.

ADDITIONAL PHENOTYPES

3.2.5 SIGNIFICANT CORRELATIONS BETWEEN PHENOTYPES AND brain DISORDERS

4. MAIN CONCLUSIONS

take-home messages

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.

outlook

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.

6. references

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).

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.

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Analysis of shared heritability

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