The American Journal of Human Genetics, Volume 106

Supplemental Data

Complete Sequence of the 22q11.2 Allele in

1,053 Subjects with 22q11.2 Deletion Syndrome

Reveals Modifiers of Conotruncal Heart Defects

Yingjie Zhao, Alexander Diacou, H. Richard Johnston, Fadi I. Musfee, Donna M.McDonald-McGinn, Daniel McGinn, T. Blaine Crowley, Gabriela M. Repetto, AnnSwillen, Jeroen Breckpot, Joris R. Vermeesch, Wendy R. Kates, M. CristinaDigilio, Marta Unolt, Bruno Marino, Maria Pontillo, Marco Armando, Fabio DiFabio, Stefano Vicari, Marianne van den Bree, Hayley Moss, Michael J. Owen, Kieran C.Murphy, Clodagh M. Murphy, Declan Murphy, Kelly Schoch, Vandana Shashi, FloraTassone, Tony J. Simon, Robert J. Shprintzen, Linda Campbell, Nicole Philip, DamianHeine-Suñer, Sixto García-Miñaúr, Luis Fernández, International 22q11.2 Brain andBehavior Consortium, Carrie E. Bearden, Claudia Vingerhoets, Therese vanAmelsvoort, Stephan Eliez, Maude Schneider, Jacob A.S. Vorstman, DoronGothelf, Elaine Zackai, A.J. Agopian, Raquel E. Gur, Anne S. Bassett, Beverly S.Emanuel, Elizabeth Goldmuntz, Laura E. Mitchell, Tao Wang, and Bernice E. Morrow

Figure S1. Plot of the top 20 eigen values for all subjects with 22q11.2DS and three subpopulations. Top five, four, four, and five PCs were used as covariates to adjust for possible population stratification in logistic regression analyses for common variants among all subjects and stratified analyses in Caucasian, Hispanic and African-admixed populations, respectively.

161 African-admixed

0

1

2

3

4

5

6CTD African American

Chromosome 22 position

-lo

g 10(p)

18500000 19000000 19500000 20000000 20500000 21000000 21500000●●

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0

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6CTD Hispanics

Chromosome 22 position

-lo

g 10(p)

18500000 19000000 19500000 20000000 20500000 21000000 21500000●

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0

1

2

3

4

5

6CHD_all regional plot among all 1053 samples

Chromosome 22 position

-lo

g 10(p)

18500000 19000000 19500000 20000000 20500000 21000000 21500000

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Hispanics subgroup

2B

2C

TBX1

CRKL

-log1

0(p)

Chromosome 22 position

0

1

2

3

4

5

6purevsdalone White

Chromosome 22 position

-lo

g 10(p)

18500000 19000000 19500000 20000000 20500000 21000000 21500000

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6asdalone6 White

Chromosome 22 position

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g 10(p)

18500000 19000000 19500000 20000000 20500000 21000000 21500000●

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VSD alone

ASD alone2D

2E

CHD2A

African-Admixed subgroup

-log1

0(p)

Chromosome 22 position

-log1

0(p)

Chromosome 22 position

TBX1

CRKL

TBX1

CRKL

Chromosome 22 position

Chromosome 22 position

-log1

0(p)

-log1

0(p)

Figure S2. Plot of logistic regression analyses of common variants for CHD risk in the remaining allele of 22q11.2 with adjustment of sex and top five PCs, stratified analyses in African-Admixed and Hispanics subgroups as well as stratified by CHD phenotypes including ASD alone and VSD alone subgroups. (A) 1,053 all samples, (B) 135 African-admixed samples, (C) 89 Hispanic samples and (D, E) Plot of logistic regression analyses of common variants for 524 ASD cases and controls and 574 VSD cases and controls. Variants in TBX1and CRKL gene regions are highlighted in green. Two vertical dashed red lines denote the top associated signals region (chr22: 20607741-20958141 in hg38); blue horizontal line represents the suggestive significant threshold (P=1.0�10-3). Four gray blocks represent LCR22A, B, C and D.

TBX1

CRKL

TBX1

CRKL

B C LCR22DLCR22A

0

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4

5

6OFT_SHF

Chromosome 22 position

-lo

g 10(p)

18500000 19000000 19500000 20000000 20500000 21000000 21500000●●

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0

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6other_aorticarch

Chromosome 22 position

-lo

g 10(p)

18500000 19000000 19500000 20000000 20500000 21000000 21500000

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Cardiac OFT defects

Aortic arch defects

-log1

0(p)

-log1

0(p)

Chromosome 22 position

Chromosome 22 position

TBX1 CRKL

LDLCR22A LCR22DCBA

B

Figure S3. Regional plot of logistic regression analyses for cardiac OFT defects and aortic arch defects, respectively. The 424 CTD cases were separated into two groups, in which one had cardiac OFT defects (TOF, PTA, PS or PA) and the other had aortic arch defects (RAA, IAAB, abnormal origin of the right or left subclavian artery). (A) Regional plot for common variants for risk of cardiac OFT defects in the remaining allele of 22q11.2 with adjustment of sex and top five PCs in 256 caseswith cardiac OFT defects versus 469 controls. (B) Regional plot for risk of aortic arch defects in 168 cases with aortic arch defects versus 469 controls. Variants in TBX1 and CRKL loci are indicated (green). Gray blocks represent LCR22A, B, C and D in the 22q11.2 region. Blue horizontal lines represent threshold of suggestive significant association for multiple testing at 1.0�10-3. Two vertical red dashed lines denote top associated variants (chr22:20607741-20958141 in Genome Assembly, hg38). Red bar indicates LD block. Variants in red survived false discovery rate (FDR) for multiple testing correction.

PI4KA SNAP29RefSeq Genes

[0 - 63]

SRR4011958.sorted.bam Coverage

[0 - 107]

SRR4011950.sorted.bam Coverage

[0 - 186]

SRR4011943.sorted.bam Coverage

[0 - 37]

SRR4011935.sorted.bam Coverage

[0 - 19]

SRR4011957.sorted.bam Coverage

[0 - 52]

SRR4011948.sorted.bam Coverage

[0 - 57]

SRR4011941.sorted.bam Coverage

[0 - 108]

SRR4011932.sorted.bam Coverage

[0 - 25]

SRR4011954.sorted.bam Coverage

[0 - 44]

SRR4011947.sorted.bam Coverage

[0 - 42]

SRR4011938.sorted.bam Coverage

[0 - 32]

SRR4011931.sorted.bam Coverage

21,206 kb 21,208 kb 21,210 kb 21,212 kb 21,214 kb 21,216 kb 21,218 kb

15 kb

chr22

p13 p12 p11.2 p11.1 q11.1 q11.21 q11.22 q11.23 q12.1 q12.2 q12.3 q13.1 q13.2 q13.31 q13.32 q13.33

file:///C:/Users/yizhao/Desktop/GH22J020855.svg

第1页 共1页 2019/10/4 10:35

CRKLRefSeq Genes

[0 - 64]

SRR4011958.sorted.bam Coverage

[0 - 110]

SRR4011950.sorted.bam Coverage

[0 - 152]

SRR4011943.sorted.bam Coverage

[0 - 36]

SRR4011935.sorted.bam Coverage

[0 - 31]

SRR4011957.sorted.bam Coverage

[0 - 49]

SRR4011948.sorted.bam Coverage

[0 - 38]

SRR4011941.sorted.bam Coverage

[0 - 79]

SRR4011932.sorted.bam Coverage

[0 - 34]

SRR4011954.sorted.bam Coverage

[0 - 27]

SRR4011947.sorted.bam Coverage

[0 - 42]

SRR4011938.sorted.bam Coverage

[0 - 30]

SRR4011931.sorted.bam Coverage

21,266 kb 21,268 kb 21,270 kb 21,272 kb 21,274 kb 21,276 kb 21,278 kb 21,280 kb

15 kb

chr22

p13 p12 p11.2 p11.1 q11.1 q11.21 q11.22 q11.23 q12.1 q12.2 q12.3 q13.1 q13.2 q13.31 q13.32 q13.33

file:///C:/Users/yizhao/Desktop/GH22J020916.svg

第1页 共1页 2019/10/4 10:33

CRKL LINC01637 AIFM3RefSeq Genes

[0 - 16]

SRR4011958.sorted.bam Coverage

[0 - 21]

SRR4011950.sorted.bam Coverage

[0 - 32]

SRR4011943.sorted.bam Coverage

[0 - 10.00]

SRR4011935.sorted.bam Coverage

[0 - 14]

SRR4011957.sorted.bam Coverage

[0 - 21]

SRR4011948.sorted.bam Coverage

[0 - 17]

SRR4011941.sorted.bam Coverage

[0 - 39]

SRR4011932.sorted.bam Coverage

[0 - 15]

SRR4011954.sorted.bam Coverage

[0 - 13]

SRR4011947.sorted.bam Coverage

[0 - 13]

SRR4011938.sorted.bam Coverage

[0 - 14]

SRR4011931.sorted.bam Coverage

21,306 kb 21,308 kb 21,310 kb 21,312 kb 21,314 kb 21,316 kb 21,318 kb 21,

15 kb

chr22

p13 p12 p11.2 p11.1 q11.1 q11.21 q11.22 q11.23 q12.1 q12.2 q12.3 q13.1 q13.2 q13.31 q13.32 q13.33

file:///C:/Users/yizhao/Desktop/rs178252.svg

第1页 共1页 2019/10/4 10:26

PI4KA SNAP29RefSeq Genes

[0 - 63]

SRR4011958.sorted.bam Coverage

[0 - 107]

SRR4011950.sorted.bam Coverage

[0 - 186]

SRR4011943.sorted.bam Coverage

[0 - 37]

SRR4011935.sorted.bam Coverage

[0 - 19]

SRR4011957.sorted.bam Coverage

[0 - 52]

SRR4011948.sorted.bam Coverage

[0 - 57]

SRR4011941.sorted.bam Coverage

[0 - 108]

SRR4011932.sorted.bam Coverage

[0 - 25]

SRR4011954.sorted.bam Coverage

[0 - 44]

SRR4011947.sorted.bam Coverage

[0 - 42]

SRR4011938.sorted.bam Coverage

[0 - 32]

SRR4011931.sorted.bam Coverage

21,206 kb 21,208 kb 21,210 kb 21,212 kb 21,214 kb 21,216 kb 21,218 kb 21,220 kb

15 kb

chr22

p13 p12 p11.2 p11.1 q11.1 q11.21 q11.22 q11.23 q12.1 q12.2 q12.3 q13.1 q13.2 q13.31 q13.32 q13.33

file:///C:/Users/yizhao/Desktop/rs112197871.svg

第1页 共1页 2019/10/4 10:39

rs178252rs112197871

PI4KA SNAP29 LINC01637 PI4KA SNAP29 CRKL

GH22J020855 GH22J020916

time point1: hiPSCs/hESCs at day 0

time point 2: Mesoderm at day 2

time point 3:Cardiac Mesoderm at day 4

Figure S4. Overlapping of top associated variants and enhancers with open chromatin regions during heart development. Two of the 69 top associated variants, rs112197871 and rs178252 (6A and 6B), as indicated by red vertical lines, reside in open chromatin regions. GH22J020855 and GH22J020916 (6C and 6D) double elite enhancers overlap with open chromatin regions as indicated by red boxes along chr22, during the differentiation from human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) to cardiac mesoderm at day 0, day 2 and day 4 based on ATAC-seq data, GSE85330 51. Genes are indicated under the ATAC-seq data. Grey peaks represent open chromatin regions.

4A 4B 4C 4D

Enriched in casesEnriched in controls OR

Figure S5. Enrichment analyses of rare variants among 14 different categories for CHD and CTD subset of case-control comparisons. The red lines against the gray violin plots denote observed ORs of the combined effect of all rare variants that mapped to each category. The violin plot represents the kernel density estimation of OR from 10,000 case-control label swapping permutations from which the significance was also assessed. Box plot illustrates median, first and third quartiles of ORs based on permutations. First number in the parentheses is the total number of variants in each category and the second number is the average number of variants per individual. ncRNA (non-coding RNA) denotes all variants in ncRNA genes. Conserved denotes all variants with a phastCons score greater that 0.9. Double elite denotes all rare variants that reside in double elite enhancers based on the GeneHancer database.

Enriched in casesEnriched in controls OR

CHD CTD

0

1

2

3

4

5

6CTD regional plot among 790 White samples

Chromosome 22 position

-lo

g 10(p)

18500000 19000000 19500000 20000000 20500000 21000000 21500000

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6

TBX1

CRKL

669 Caucasian samples

Figure S6. Plot of result of Fisher’s exact test for rare variants versus CTD risk in the remaining allele of 22q11.2 in 669 Caucasian samples. Variants in TBX1 and CRKL are highlighted in green. Blue horizontal line represents suggestive corrected significant threshold for multiple testing at P= 1.0�10-3. The two vertical dashed lines denote where the top associated signals reside (chr22: 20607741-20958141 in hg38). Four gray blocks represent LCR22A, B, C and D.

-log1

0(p)

Chromosome 22 position

Figure S7. Set-based analyses burden test for rare variants. Burden test with adjustment of sex and top four PCs for CTD risk was applied to rare variants in 669 Caucasian subjects. Set includes all 72 genes (between TSS and TTS plus 2 kb region both upstream and downstream) between LCR22A-D, 72 promoters of genes (both 2kb upstream and downstream of TSS) and 96 curated double elite set of enhancers in the 22q11.2 region. Pink background highlights TBX1 and CRKL. Four gray blocks represent LCR22A, B, C and D. Two blue horizontal lines represent suggestive and Bonferroni corrected significant thresholds for multiple testing at 2.5×10-3 and 2.1�10-4, respectively. The two vertical red dashed lines denote where the top associated signals reside from logistic regression analyses (chr22: 20607741-20958141 in hg38).

Supplemental Information

Funding Ms. D.M. McDonald McGinn was supported by NIH R01HL084410, U01MH101720 and P01HD070454. Dr. Repetto was supported by NIH U01MH101720 and Fondecyt.-Chile grants 1130392 and 1171014. Drs. Zhao, Swillen, Philip, Kates, Johnston, Shashi, Campbell, Philip, Miñaúr, van Amelsvoort, Armando, Vorstman were supported by U01MH101720. Dr. Breckpot is funded by a senior clinical investigator fellowship of FWO Flanders. Dr. Vermeesch was supported by Fonds Wetenschappelijk Onderzoek[GOE1117N]. Drs. van den Bree and Owen were funded by NIH grant UO1MH101724, Medical Research Council (MR/N022572/1 and MR/L011166/1)(IMAGINE-ID study), the Baily Thomas Charitable Trust (2315/1), the Waterloo Foundation (918-1234), a WellcomeTrust ISSF grant, Wellcome Trust Strategic Award (503147; Owen), Health & Care Research Wales (Welsh Government, 507556), Medical Research Council Centre grant (G0801418) and Medical Research Council Programme grant (G0800509). Dr. Simon was supported by NIH U01MH101720, R01HD042974, R01MH107108 and U54HD079125 Dr. K. Murphy was supported by Health Research Board of Ireland (HRB) grant HRA-POR-2015-1077. Dr. D. Murphy was funded by the NIHR Maudsley Biomedical Research Centre in Mental Health and the EU Innovative Medicines Initiative (EU AIMS-2-TRIALS). Grant No. 777394. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation program, the European Federation of Pharmaceutical Industry Associations, Autism Speaks, Autistica, and the Simons Foundation Autism Research Initiative. Dr. Heine-Suñer was supported by a Spanish Government ISCIII grant PI1302278 (Co-funded by European Regional Development Fund/European Social Fund) "Investing in your future") Dr. Bearden was supported by NIMH RO1MH08593, U01MH101719 and R21MH116473. Dr. Eliez was supported by the Swiss National Science Foundation (Grant numbers: 324730_144260 and 51NF40-185897). Dr. Gur was supported by NIH grant U01MH101719, U01MH101720 and R01 MH0087626. Drs. Gothelf and Gur were supported by the Binational Science Foundation, grant 2017369. Drs. Goldmuntz, Mitchell, Agopian and Musfee were supported by P01 HD070454. Drs. Goldmuntz, Mitchell and Agopian were also supported by NIH grants: P01HD070454, P50-HL74731), Pediatric Cardiac Genomics Consortium (U01-HL098188, U01HL131003, U01HL098147, U01HL098153, U01HL098163, U01HL098123, U01HL098162, U01HL09003); U54HG006504); M01RR-000240, RR024134; and UL1TR000003. Dr. Bassett was supported by the Dalglish Chair in 22q11.2 Deletion Syndrome, the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, Canadian Institutes of Health Research funding (MOP-97800 and MOP-89066), NIH U01MH101720 and the University of Toronto McLaughlin Centre. Dr. Emanuel was supported by NIH R01HL084410, U01MH101720 and P01HD070454. Dr. Wang was supported by NIH R21HL118637, R01HL084410, U01MH101720 and P01HD070454. Dr. Epstein was supported by NIH U01MH101720 and R01GM117946. Dr. Warren was supported by U01MH101720.