Supplemental Information. Common Variant Burden Contributes. to the Familial Aggregation. of Migraine in 1,589 Families

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1 Neuron, Volume 98 Supplemental Information Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families Padhraig Gormley, Mitja I. Kurki, Marjo Eveliina Hiekkala, Kumar Veerapen, Paavo Häppölä, Adele A. Mitchell, Dennis Lal, Priit Palta, Ida Surakka, Mari Anneli Kaunisto, Eija Hämäläinen, Salli Vepsäläinen, Hannele Havanka, Hanna Harno, Matti Ilmavirta, Markku Nissilä, Erkki Säkö, Marja-Liisa Sumelahti, Jarmo Liukkonen, Matti Sillanpää, Liisa Metsähonkala, Seppo Koskinen, Terho Lehtimäki, Olli Raitakari, Minna Männikkö, Caroline Ran, Andrea Carmine Belin, Pekka Jousilahti, Verneri Anttila, Veikko Salomaa, Ville Artto, Markus Färkkilä, 23andMe Research Team, International Headache Genetics Consortium (IHGC), Heiko Runz, Mark J. Daly, Benjamin M. Neale, Samuli Ripatti, Mikko Kallela, Maija Wessman, and Aarno Palotie

2 Supplemental Information Table of contents 1. Supplemental Tables Supplemental Figures

3 1. Supplemental Tables Table S1. Size of families in the migraine family collection. Pedigree size is the total number of individuals in a family (affected plus unaffected). Related to Figure S1 and STAR Methods. Pedigree size No. of families No. of individuals ,061 Total: 1,589 8,319 2

4 Table S2. Comparing polygenic risk scores (PRS) between migraine subtypes. Each row in the table tested if the PRS was different between cases from two migraine subtypes (subtype 1 vs. subtype 2) using a logistic mixed model that was adjusted for relatedness (i.e. including the GRM as a random effect), sex, and age. OR is the odds ratio for one standard deviation (SD) increase in PRS. CI is confidence intervals. Related to Figure 2 and Table 1. Subtype 1 Subtype 2 N (subtype 1) N (subtype 2) OR (of PRS) 95% CI P-value (Wald test) Migraine with typical aura Migraine without aura (MO) 2,420 2, [ ] Hemiplegic migraine (HM) Migraine without aura (MO) 540 2, [ ] Hemiplegic migraine (HM) Migraine with typical aura 540 2, [ ] 0.09 Typical aura with headache Typical aura without headache 2, [ ] Familial hemiplegic migraine (FHM) Sporadic hemiplegic migraine (SHM) [ ] 0.58 Families: no migraine FINRISK population cases 3,002 1, [ ]

5 Table S3. Variance explained (observed scale) by the polygenic risk score (PRS) across a range of PRS P-value thresholds. Odds ratios (ORs) and Nagelkerke s R2 were estimated from logistic mixed models that were adjusted for sex, age, age 2, age 3, and genetic relatedness. CI is the confidence interval. Related to Figure S3 and STAR Methods. Phenotype Cases Controls FINRISK: population cases 1,101 13,369 Families: any migraine 5,317 13,369 Families: migraine without aura 2,357 13,369 Families: migraine with typical aura 2,420 13,369 Families: hemiplegic migraine ,369 PRS p-value Nagelkerke s OR 95% CI threshold R 2 < 5e < 1e < 1e < 1e < 1e < 1e < < < < < < 5e < 1e < 1e < 1e < 1e < 1e < < < < < < 5e < 1e < 1e < 1e < 1e < 1e < < < < < < 5e < 1e < 1e < 1e < 1e < 1e < < < < < < 5e < 1e < 1e < 1e < 1e < 1e < < <

6 Table S4. Analysis of the migraine subtypes within families using population controls split by quartiles of the polygenic risk score (PRS) distribution in the FINRISK population controls. Individuals in the lowest quartile of the PRS distribution were used as the reference group, which included; 765 cases (any migraine), 365 cases (migraine without aura), 330 cases (migraine with typical aura), 70 cases (hemiplegic migraine), and 712 controls. Related to Table 2. Phenotype N (cases) N (controls) PRS Quartile tested (vs. 1 st quartile) OR 95% CI P-value (Wald test) st (ref group) NA NA NA Any migraine 1, nd , rd , th st (ref group) NA NA NA Migraine without aura nd rd th st (ref group) NA NA NA Migraine with typical aura nd rd th st (ref group) NA NA NA Hemiplegic migraine nd rd th

7 Table S5. Comparison of polygenic risk score (PRS) burden in familial migraine cases to FINRISK population cases. Effect size (OR) of one standard deviation (SD) increase in PRS when comparing each clinical migraine subtype from the family sample to the population-based cases from FINRISK. CI is confidence interval. Related to Figure 2 and Table 1. Phenotype Total N N(familial cases) N(population cases) OR 95% CI P-value Any migraine 6,418 5,317 1, [ ] Migraine without aura 3,458 2,357 1, [ ] Migraine with aura 4,061 2,960 1, [ ] Migraine with typical aura 3,521 2,420 1, [ ] Typical aura without headache 1, , [ ] Typical aura with headache 3,164 2,350 1, [ ] Hemiplegic migraine 1, , [ ] Familial hemiplegic migraine 1, , [ ] Sporadic hemiplegic migraine 1, , [ ]

8 Table S6. Association of polygenic risk score (PRS) to other traits of interest. Odds ratio (OR) of PRS as a variable in logistic mixed model in clinical phenotypes with migraine subtypes as outcomes. The PRS were scaled to FINRISK population mean. CI is confidence interval. Related to Figure 4. Trait Total N N (trait==1) N (trait==0) OR 95% CI P-value Sex (males==1) 5,317 1,295 4, Index case 5,317 1,483 3, Triptan use 5,317 1,456 3, Age at onset < 20 years old 5,317 3,631 1,

9 Table S7: Polygenic risk score (PRS) transmission disequilibrium test (ptdt) in migraine subtypes. For this analysis the family sample was subset into parent-offspring trios and grouped by the phenotype of the offspring. The ptdt deviation is the mean standard deviation (of the PRS observed in the offspring) from the expected mean PRS that would be transmitted from the parents. CI is confidence interval. Related to Figure 3. Phenotype Group N ptdt Deviation P-value 95% CI Unaffected offspring Any migraine (affected offspring) Migraine without aura (affected offspring) Migraine with typical aura (affected offspring) Hemiplegic migraine (affected offspring)

10 Table S8. FHM individuals from 4 families carrying a pathogenic Mendelian variant. 17 individuals from these families were diagnosed with FHM, 14 out of 17 carried a previously reported missense mutation for FHM. Of the three FHM cases without a pathogenic variant, one had high polygenic load and two remain unexplained. Pathogenic variants were confirmed by either whole-exome or Sanger sequencing. PRS Quartile is the number of the polygenic risk score (PRS) quartile for that individual compared to the PRS distribution observed in the FINRISK population controls. Related to Table 2, Figure S7, and Figure S8. Family ID Individual ID SEX AGE PRS (P<0.1) Onset bin PRS Quartile High PRS (>75th) Very high PRS (>90th) Pathogenic mutation Pathogenic variant ID Gene F p.thr665met rs CACNA1A F TRUE TRUE F >20 4 TRUE - p.thr665met rs CACNA1A F TRUE TRUE p.thr665met rs CACNA1A F p.ala606thr 1: :A_G ATP1A F >20 4 TRUE - p.ala606thr 1: :A_G ATP1A F F p.thr345ala rs ATP1A F p.thr345ala rs ATP1A F p.thr345ala rs ATP1A M p.thr345ala rs ATP1A F p.thr345ala rs ATP1A F p.thr345ala rs ATP1A F TRUE TRUE p.thr345ala rs ATP1A M M > p.arg383his rs ATP1A F p.arg383his rs ATP1A2 9

11 Table S9. Association of polygenic risk score (PRS) to clinical diagnostic symptoms of migraine. Odds ratio (OR) of PRS as a variable in logistic mixed model in clinical phenotypes with migraine subtypes as outcomes. The PRS were scaled to FINRISK population mean. CI is confidence interval. Related to Figure 4 and Figure S9. Diagnostic symptom Total N N (symptom==1) N (symptom==0) OR 95% CI P-value (Wald test) Nagelkerke's R 2 Attack length > 4 hours 5,317 4,167 1, Unilaterality 5,317 3,506 1, Pulsation 5,317 3,202 2, Intensity: Moderate/Severe 5,317 4, Aggravation by physical exercise 5,317 3,864 1, Nausea 5,317 4, Vomiting 5,317 3,006 2, Phonophobia 5,317 4,103 1, Photophobia 5,317 4,

12 Table S10. Characteristics of the Finnish migraine family collection. N is the number of individuals with each phenotype (out of all 1,589 families). PRS is the polygenic risk score, SD is the standard deviation, MwoA means the individuals sometimes has attacks of migraine without aura, MwA means the patient sometimes has attacks of migraine with aura, HM means the patient sometimes has attacks of Hemiplegic Migraine. Related to Table 1 and STAR Methods. All individuals No migraine Any migraine Migraine without aura Migraine with aura Migraine with typical aura Typical aura without headache Typical aura with headache Hemiplegic migraine Hemiplegic migraine, sporadic Hemiplegic migraine, familial N 8,319 3,002 5,317 2,357 2,960 2, , Age (mean (SD)) (18.24) (18.33) (18.19) (17.95) (18.38) (18.52) (19.48) (18.50) (17.72) 42.9 (18.1) 44.8 (17.1) Sex = Male (%) 2,982 ( 35.8) 1,687 ( 56.2) 1,295 ( 24.4) 600 ( 25.5) 695 ( 23.5) 612 ( 25.3) 37 ( 52.9) 575 ( 24.5) 83 ( 15.4) 40.0 (11.7) 43.0 (21.8) PRS (mean (SD)) 0.28 (1.02) 0.06 (1.01) 0.41 (1.01) 0.32 (0.99) 0.48 (1.03) 0.47 (1.03) (0.94) 0.47 (1.03) 0.54 (0.99) 0.56 (0.98) 0.51 (1.00) Index case (%) 1,568 ( 18.8) 85 ( 2.8) 1,483 ( 27.9) 561 ( 23.8) 922 ( 31.1) 636 ( 26.3) 3 ( 4.3) 633 ( 26.9) 286 ( 53.0) 233 (67.9) 53 ( 26.9) Original index case (%) 961 ( 90.7) 28 ( 47.5) 933 ( 93.3) 334 ( 93.6) 599 ( 93.2) 405 ( 91.4) 1 (100.0) 404 ( 91.4) 194 ( 97.0) 152 (96.8) 42 ( 97.7) Triptans use (%) 1,505 (18.1) 49 (1.6) 1,456 (27.4) 617 (26.2) 839 (28.3) 590 (24.4) 1 (100.0) 589 (100.0) 249 (46.1) 183 (53.4) 66 (33.5) MwoA (%) 4,943 ( 59.4) 0 ( 0.0) 4,943 ( 93.0) 2,357 (100.0) 2,586 ( 87.4) 2,063 ( 85.2) 0 ( 0.0) 2063 ( 87.8) 523 ( 96.9) 330 (96.2) 193 (98.0) MwA (%) 2,885 ( 34.7) 0 ( 0.0) 2,885 ( 54.3) 0 ( 0.0) 2,885 ( 97.5) 2,420 (100.0) 70 (100.0) 2350 (100.0) 465 ( 86.1) 285 (83.1) 180 ( 91.4) HM (%) 540 ( 6.5) 0 ( 0.0) 540 ( 10.2) 0 ( 0.0) 540 ( 18.2) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 540 (100.0) 343 (100.0) 197 (100.0) Photophobia (%) 5,181 ( 62.3) 414 ( 13.8) 4,767 ( 89.7) 2,119 ( 89.9) 2,648 ( 89.5) 2,120 ( 87.6) 0 ( 0.0) 2120 ( 90.2) 528 ( 97.8) 333 (97.1) 195 ( 99.0) Phonophobia (%) 4,445 ( 53.4) 342 ( 11.4) 4,103 ( 77.2) 1,814 ( 77.0) 2,289 ( 77.3) 1,794 ( 74.1) 0 ( 0.0) 1794 ( 76.3) 495 ( 91.7) 311 (90.7) 184 ( 93.4) Unilaterality (%) 3,875 ( 46.6) 369 ( 12.3) 3,506 ( 65.9) 1,469 ( 62.3) 2,037 ( 68.8) 1,579 ( 65.2) 2 ( 2.9) 1577 ( 67.1) 458 ( 84.8) 295 (86.0) 163 ( 82.7) Pulsation (%) 3,547 ( 42.6) 345 ( 11.5) 3,202 ( 60.2) 1,469 ( 62.3) 1,733 ( 58.5) 1,369 ( 56.6) 1 ( 1.4) 1368 ( 58.2) 364 ( 67.4) 225 (65.6) 139 ( 70.6) Nausea (%) 4,786 ( 57.5) 300 ( 10.0) 4,486 ( 84.4) 2,056 ( 87.2) 2,430 ( 82.1) 1,935 ( 80.0) 0 ( 0.0) 1935 ( 82.3) 495 ( 91.7) 311 (90.7) 184 ( 93.4) Vomiting (%) 3,083 ( 37.1) 77 ( 2.6) 3,006 ( 56.5) 1,325 ( 56.2) 1,681 ( 56.8) 1,300 ( 53.7) 0 ( 0.0) 1300 ( 55.3) 381 ( 70.6) 235 (68.5) 146 ( 74.1) Attack length over 4h (%) 4,500 ( 54.1) 333 ( 11.1) 4,167 ( 78.4) 1,914 ( 81.2) 2,253 ( 76.1) 1,771 ( 73.2) 0 ( 0.0) 1771 ( 75.4) 482 ( 89.3) 304 (88.6) 178 ( 90.4) Intensity moderate or severe (%) 5,426 ( 65.2) 605 ( 20.2) 4,821 ( 90.7) 2,201 ( 93.4) 2,620 ( 88.5) 2,103 ( 86.9) 1 ( 1.4) 2102 ( 89.4) 517 ( 95.7) 329 (95.9) 188 ( 95.4) Aggravation by physical exercise (%) 4,151 ( 49.9) 287 ( 9.6) 3,864 ( 72.7) 1,782 ( 75.6) 2,082 ( 70.3) 1,640 ( 67.8) 2 ( 2.9) 1638 ( 69.7) 442 ( 81.9) 284 (82.8) 158 ( 80.2) Age at onset under 20 years (%) 4,179 ( 50.2) 548 ( 18.3) 3,631 ( 68.3) 1,599 ( 67.8) 2,032 ( 68.6) 1,604 ( 66.3) 5 ( 7.1) 1599 ( 68.0) 428 ( 79.3) 261 (76.1) 167 ( 84.8) Age of onset bin (%) 0-5 years 193 ( 3.9) NA 193 ( 3.9) 96 ( 4.4) 97 ( 3.5) 64 ( 2.9) 0 ( 0.0) 64 ( 2.9) 33 ( 6.2) 20 ( 6.0) 13 ( 6.6) 5-10 years 1,102 ( 22.4) NA 1,102 ( 22.4) 519 ( 23.7) 583 ( 21.3) 448 ( 20.3) 1 ( 14.3) 447 ( 20.3) 135 ( 25.3) 75 ( 22.3) 60 ( 30.5) years 1,402 ( 28.4) NA 1,402 ( 28.4) 576 ( 26.3) 826 ( 30.1) 641 ( 29.0) 1 ( 14.3) 640 ( 29.1) 185 ( 34.7) 111 ( 33.0) 74 ( 37.6) years 990 ( 20.1) NA 990 ( 20.1) 432 ( 19.7) 558 ( 20.4) 473 ( 21.4) 3 ( 42.9) 470 ( 21.3) 85 ( 15.9) 61 ( 18.2) 24 ( 12.2) >20 years 1,243 ( 25.2) NA 1,243 ( 25.2) 565 ( 25.8) 678 ( 24.7) 583 ( 26.4) 2 ( 28.6) 581 ( 26.4) 95 ( 17.8) 69 ( 20.5) 26 ( 13.2) 11

13 Table S11. Summary of genotyping batches for samples from the Finnish migraine family collection and FINRISK. Samples were genotyped in seven batches, quality control (QC) performed independently on each batch, and then merged one-by-one, with QC repeated on each merged dataset. Related to STAR Methods. Batch Cohort No. of samples Chip 1 Migraine family collection 2,259 Core-exome 2 Migraine family collection 6,716 Psych-chip 3 FINRISK 2,613 Core-exome 4 FINRISK 2,327 Core-exome 5 FINRISK 4,204 Core-exome 6 FINRISK 3,380 Core-exome 7 FINRISK 2,309 Core-exome 12

14 Table S12. List of genome-wide association studies (GWAS) of migraine that were included in the metaanalysis to calculate the weights used in the polygenic risk score (PRS). All four GWAS studies containing samples from Finland were excluded. Related to STAR Methods. Study ID Full Name of GWAS Cases Controls Included in estimation of PRS betas 23andMe 23andMe Inc. 30, ,147 Yes ALSPAC Avon Longitudinal Study of Parents and Children 3,134 5,103 Yes ATM Australian Twin Migraine 1,683 2,383 Yes B58C 1958 British Birth Cohort 1,165 4,141 Yes Danish HC Danish Headache Center 1,771 1,000 Yes DeCODE decode Genetics Inc. 3,135 95,585 Yes Dutch MA Dutch migraine with aura 734 5,211 Yes Dutch MO Dutch migraine without aura 1,115 2,028 Yes EGCUT Estonian Genome Center, University of Tartu 813 9,850 Yes Finnish MA Finnish migraine with aura 933 2,715 Excluded German MA German migraine with aura 1,071 1,010 Yes German MO German migraine without aura 1,160 1,647 Yes Health 2000 Health ,764 Excluded HUNT Nord-Trøndelag Health Study 1,395 1,011 Yes NFBC Northern Finland Birth Cohort 756 4,393 Excluded NTR/NESDA Netherlands Twin Register and the Netherlands Study of Depression and Anxiety 1,636 3,819 Yes Rotterdam III Rotterdam Study III 487 2,175 Yes Swedish Twins Swedish Twin Registry 1,307 4,182 Yes Tromsø The Tromsø Study 660 2,407 Yes Twins UK Twins UK 618 2,334 Yes WGHS Women s Genome Health Study 5,122 18,108 Yes Young Finns Young Finns 378 2,065 Excluded Published GWAS total: 59, ,078 Total used for PRS (after exclusions): 57, ,141 13

15 2. Supplemental Figures Figure S1. Histogram of family sizes in the migraine family collection. The pedigree size is the total number of individuals in a family (affected plus unaffected). The vertical axis shows the number of independent families that were collected for analysis for each pedigree size bin. Related to Table S1 and STAR Methods. 14

16 Figure S2. Effect size of polygenic risk scores (PRS) in subtypes of migraine with aura (MA). Odds ratios were calculated for the PRS in each subtype from the family sample compared to the FINRISK population controls (n = 13,369) using a logistic mixed-model adjusted for genetic relatedness, sex and age. The PRS was calculated using published migraine GWAS data (N=375,000, see Methods) excluding Finnish samples and after LD-clumping to obtain an independent set of 38,872 SNPs (with P-values < 0.1). CIs are confidence intervals. Related to Figure 2 and Table 1. 15

17 Figure S3. Variance explained by the polygenic risk score (PRS) on the observed scale. Nagelkerke s pseudo-r 2 was estimated using logistic mixed models that were fitted with and without the PRS for each migraine sample and subtype. Models were adjusted for sex, age, age 2, and age 3 (as fixed effects) and genetic relatedness (as random effects). Note that variance explained is given only the observed scale because the transformation to the liability scale is non-trivial for samples with family-based ascertainment. Related to Table S3 and STAR Methods. 16

18 Cases Controls OR 95% CI P-value 378 2, E-4 1,307 4, E , E , E-4 1,101 13, E-17 5,317 13, E-109 Figure S4. Enrichment of the polygenic risk score (PRS) in migraine cases from five different population-based studies. The Young Finns (OR=1.21, 95CI= , P=8,7e-4), Swedish Twins (OR=1.24, 95CI= , P=1.8e-11), Northern Finland Birth Cohort (OR=1.20, 95CI= , P=1.1e-5), and Health 2000 (OR=1.40, 95CI= , P=1.6e-4). The higher enrichment observed for the Finnish migraine families is also shown for comparison. Related to Figure 2 and STAR Methods. 17

19 Cases Controls OR 95% CI P-value 1,101 13, ,101 13, ,317 13, ,317 13, Figure S5. Polygenic risk scores (PRS) for Intelligence Quotient (IQ) and Schizophrenia (SCZ). No enrichment for either the IQ-PRS or the SCZ-PRS was found in either the migraine family cases or in the FINRISK population cases confirming that there was no systematic bias between these two samples that might have contributed to the enrichment differences observed for the migraine PRS. Related to Figure 2. 18

20 Figure S6. Comparison of polygenic risk score (PRS) profiles from the familial migraine cases to healthregistry identified migraine cases from the general population. The Clinical, multiplex familial migraine group represents all migraine cases taken from the Finnish migraine families (n = 5,317). The FINRISK any migraine group is all migraine cases in FINRISK identified via health registry data (n = 1,101). The Triptans subgroups are those FINRISK cases that have prescription use data. The Outpatients subgroups are those FINRISK cases who have visited an outpatient clinic for migraine in combination with their prescription use data. Related to Figure 2 and Table 1. 19

21 A B Figure S7. Number of individuals from the 74 FHM families with high polygenic risk scores (PRS) among (A) the FHM-affected individuals, and (B) the unaffected family members. Individuals were categorized as high PRS if their score was in the 75th percentile of the PRS distribution in the FINRISK population. *An asterisk marks the four families that contain cases carrying a rare Mendelian variant in one of the known FHM genes (CACNA1A, ATP1A2, SCN1A). Related to Table 2, Table S8, and Figure S8. 20

22 Figure S8. Boxplots per family of the Polygenic Risk Score (PRS) in each of the 74 FHM families. The horizontal axis is Family ID ordered by the mean PRS of each family. The four families carrying a known pathogenic variant are highlighted in grey (note that we have not yet sequenced all families to identify all pathogenic variant carriers). The black vertical dashed line is the mean PRS of the FINRISK population controls. The red vertical dashed lines indicate the lower and upper quartiles of PRS of the FINRISK population controls. Related to Table 2, Table S8, and Figure S7. 21

23 Figure S9. Correlation structure between the clinical diagnostic variables of migraine. The color of squares in the heatmap represent Pearson s correlation coefficient calculated between each variable. Related to Figure 4 and Table S9. 22