Download Dissociation of accumulated genetic risk and disease

Supplementary Information
Dissociation of accumulated genetic risk and disease
severity in patients with schizophrenia
Sergi Papiol, Ph.D.1,2,3, Dörthe Malzahn, Ph.D.4, Anne Kästner, M.Sc.1,
Swetlana Sperling, B.A.1, Martin Begemann, M.D.1, Hreinn Stefansson, Ph.D. 5,
Heike Bickeböller, Ph.D.4, Klaus-Armin Nave, Ph.D.2,3 and Hannelore Ehrenreich, M.D.1,3 §
1Division
of Clinical Neuroscience, Max Planck Institute of Experimental Medicine,
2Department
3DFG
of Neurogenetics, Max Planck Institute of Experimental Medicine,
Research Center for Molecular Physiology of the Brain (CMPB),
4Department
of Genetic Epidemiology, Medical Center, Georg-August-University,
Göttingen, Germany
5deCODE
genetics, Reykjavik, Iceland.
Outline:
Supplementary Tables 1-2
Supplementary Figures 1-3
1
GRAS SAMPLE
Supplementary Table 1: GRAS patient sample description.
Variable
Mean ± s.d.
Median
Age in GRAS patients (years)
39.54 ± 12.55
39.05
PANSS positive
13.76 ± 6.32
12.00
PANSS negative
18.23 ± 7.86
17.00
Cognitive score
-0.01 ± 0.85
0.02
Total CNI
19.76 ± 18.63
15.00
Prodromal Age of Onset (years)
22.81 ± 8.70
20.00
PANSS general
33.73 ± 11.83
32.00
GAF
45.73 ± 17.26
45.00
Premorbid Intelligence
26.13 ± 6.15
27.00
Gender proportion
66.7% men / 33.3% women
-
Gender and age distribution in the sample of patients (GRAS, n=1041). Mean ± s.d. and Median of the
phenotypical variables analyzed in the GRAS sample.
2
Supplementary Table 2: PGAS: Association between cumulative genetic load
and expected value of quantitative schizophrenia-relevant phenotypes
Multivariate phenotype#
PANSS positive
PANSS negative#
PGAS
Cognitive score#
Total CNI#
Prodromal Onset
PANSS general
GAF#
Premorbid Intelligence‡
Effect per unit increase of genetic load
0.0083
P value
0.3391
Effect per unit increase of genetic load
0.0106
P value
0.4557
Effect per unit increase of genetic load
0.0333
P value
0.0220
Effect per unit increase of genetic load
0.0033
P value
0.7745
Effect per unit increase of genetic load
0.0111
P value
0.4163
Effect per unit increase of genetic load
-0.0051
P value
0.7502
Effect per unit increase of genetic load
0.0216
P value
0.1445
Effect per unit increase of genetic load
0.0122
P value
0.4073
Effect per unit increase of genetic load
0.0014
P value
0.9248
#
Corrected for age: PANSS negative, cognitive score, total CNI (for separate analyses and within multivariate phenotype); GAF.
Corrected for language problems: premorbid intelligence (886 with no language problems, 107 with correction for language
problems).
‡
Analysis based on the GRAS sample of schizophrenic patients, i.e. n=1010 individuals with complete
genotype information for 10 GWAS loci. The cumulative genetic load is defined as sum of the number
of all GWAS risk variants at the 10 loci of Table 1. Estimated was the mean effect of the genetic load
per unit increase (additive model with equal weighting of risk variants at each locus). Phenotypes were
standardized to zero mean and variance one and presented such that larger values correspond to
better performance (i.e. PANSS scores and total CNI were multiplied by -1). General PANSS, GAF
and premorbid intelligence were included in the analyses as disease control variables. A positive
estimate of the effect of increased genetic load suggests a milder phenotype, a negative estimate a
more severe phenotype. Effect size is quantified relative to trait variability (standard deviation). P
values below 0.05 were highlighted for optical guidance but are not significant due to multiple-testing
adjustment. Exploratory exclusion of non-Caucasian subjects from the GRAS sample (n=48; 4.5%) did
not qualitatively alter any of the main findings in this Table.
3
Supplementary Figure 1
Distribution of phenotype severity and cumulative genetic load with respect to the
number of GWAS-identified ‘top-10’ risk SNP alleles in the GRAS population (bar graph). Phenotype
severity in each of the figures is based on one of the 5 core items of schizophrenia. Score range for
each item in the GRAS sample is divided into 3 equal parts and ranked as mild, medium and severe
phenotype, respectively.
4
Supplementary Figure 2
Percentage distribution of phenotype severity in genetic load groups with respect
to the number of GWAS-identified ‘top-10’ risk SNP alleles in the GRAS population. Phenotype
severity is based on a composite score of 5 core features of schizophrenia (compare inset of Figure
1). Score range in the GRAS sample is divided into 3 equal parts and ranked as mild, medium and
severe disease phenotype.
5
Supplementary Figure 3
Distribution of cumulative genetic load in Icelandic and German populations
Grouping the distribution of accumulated risk genotypes in the Icelandic GWAS sample (n=582
schizophrenic individuals) yields a pattern similar to the GRAS population (n=1041), further supporting
the validity of the GRAS sample for the PGAS approach to the GWAS hits. German healthy controls
are from the GRAS case-control study (n=1144).
6