A sex-specific evolutionary interaction between ADCY9 and CETP

  1. Isabel Gamache
  2. Marc-André Legault
  3. Jean-Christophe Grenier
  4. Rocio Sanchez
  5. Eric Rhéaume
  6. Samira Asgari
  7. Amina Barhdadi
  8. Yassamin Feroz Zada
  9. Holly Trochet
  10. Yang Luo
  11. Leonid Lecca
  12. Megan Murray
  13. Soumya Raychaudhuri
  14. Jean-Claude Tardif
  15. Marie-Pierre Dubé
  16. Julie Hussin  Is a corresponding author
  1. Université de Montréal, Canada
  2. Montreal Heart Institute, Canada
  3. Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre, Canada
  4. Center for Data Sciences, Brigham and Women’s Hospital, Harvard Medical School, United States
  5. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, United States
  6. Socios En Salud, Peru
  7. Harvard Medical School, United States
  8. Centre for Genetics and Genomics Versus Arthritis, Manchester Academic Health Science Centre, University of Manchester, United Kingdom
  9. Department of Biomedical Informatics, Harvard Medical School, United States
  10. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, United States
21 figures, 8 tables and 1 additional file

Figures

Flowchart of experimental design and main results.

The four main steps of the analyses conducted in this study are reported along with the datasets used for each step and the genetic loci on which the analyses are performed. Green colored boxes …

Natural selection signature at rs1967309 in ADCY9.

(a) Genotype frequency distribution of rs1967309 in populations from the 1000 Genomes (1000G) Project and in Native Americans (NAGD). (b) Significant iHS values (absolute values above 2) for 1000G …

Figure 2—source data 1

Source file for genotype frequency distribution of rs1967309.

This file contains the genotype frequency of rs1967309 for each subpopulation from 1000G and NAGD, with the number of individuals by subpopulation.

https://cdn.elifesciences.org/articles/69198/elife-69198-fig2-data1-v2.txt
Figure 2—source data 2

Source file for iHS plot in the ADCY9 gene.

This file contains the iHS values for each position in the ADCY9 gene for each population of the 1000G dataset.

https://cdn.elifesciences.org/articles/69198/elife-69198-fig2-data2-v2.txt
Figure 2—source data 3

Source file for PBS plots in the ADCY9 gene.

This file contains the PBS value for PEL, MXL, and CHB for each position in the ADCY9 gene.

https://cdn.elifesciences.org/articles/69198/elife-69198-fig2-data3-v2.txt
Figure 3 with 2 supplements
Long-range linkage disequilibrium between rs1967309 and rs158477 in Peruvians from Lima, Peru.

(a) Genotype correlation (r2) between rs1967309 and all SNPs with MAF >5% in CETP, for the PEL population. (b) Genotype correlation between the three loci identified in (a) to be in the 99th …

Figure 3—source data 1

R2 values of all SNPs between ADCY9 and CETP genes in the PEL population from 1000G.

This file contains the result from the geno-r2 command of the vcftools software for all SNPs (MAF >5%) of the PEL population between ADCY9 and CETP genes. The script to create Figure 3a and b can be found here .

https://cdn.elifesciences.org/articles/69198/elife-69198-fig3-data1-v2.txt
Figure 3—source data 2

Source file for genotype frequency distribution of rs158477.

This file contains the genotype frequency of rs158477 for each subpopulation from 1000G and NAGD, with the number of individuals by subpopulation.

https://cdn.elifesciences.org/articles/69198/elife-69198-fig3-data2-v2.txt
Figure 3—source data 3

R2 values used for the null distribution in the PEL population from 1000G.

3,513 pairs of SNPs on chromosome 1–18 with a MAF between 15% and 30%, separated by between 50 and 60 Mb and 51–71 cM based on the PEL genetic map from 1000G. R2 values were obtained from the geno-r2 command of the vcftools software.

https://cdn.elifesciences.org/articles/69198/elife-69198-fig3-data3-v2.txt
Figure 3—figure supplement 1
Long-range linkage disequilibrium in the Andean population from the Native Population (n = 88) (a,b) and in the LIMAA cohort (n = 3243) (c,d).

(a,c) Genotype correlation (r2) between rs1967309 and all SNPs with MAF >5% in CETP. (b,d) Genotype correlation between the three loci identified in Figure 3a to be in the 99th percentile and all …

Figure 3—figure supplement 2
Comparison of genotype correlation between Peruvian from 1000G and from the LIMAA cohort.

Comparison of genotype correlation (r2) between all SNPs in ADCY9 and CETP with MAF >5% in the Peruvian population (PEL) in 1000G (x axis) and LIMAA cohort (y axis). Colored dots represent the value …

Figure 4 with 3 supplements
Sex-specific long-range linkage disequilibrium.

Genotype correlation between the loci identified in CETP in Figure 3a and all SNPs with MAF >5% in ADCY9 for (a,b) the PEL population and (c,d) LIMAA cohort in males (a,c) and in females (b,d). …

Figure 4—source data 1

R2 values of all SNPs between ADCY9 and CETP genes in the PEL population from 1000G and LIMAA cohort in male and female.

This zip archive contains all files of r2 values obtained from the geno-r2 command of the vcftools software for all SNPs (MAF >5%) of the PEL population (files beginning by F4a [male] and F4b [female]) and the LIMAA cohort (files beginning by F4c [male] and F4d [female]) between ADCY9 and CETP genes stratified by sex. Scripts to create those figures can be found here: Gamache, 2021.

https://cdn.elifesciences.org/articles/69198/elife-69198-fig4-data1-v2.zip
Figure 4—figure supplement 1
Genotype frequency distribution per sex.

Genotype frequency distribution of rs1967309 in ADCY9 (a,b) and rs158477 in CETP (c,d) in populations from the 1000 Genomes (1000G) Project, in Native Americans (NAGD) and LIMAA cohorts, in females …

Figure 4—figure supplement 2
PBS values in the ADCY9 per sex, comparing the CHB (outgroup), MXL and PEL.

Horizontal lines represent the 95th percentile PBS value of the chromosome 16 for each population for each sex. Vertical black lines represent the LD block around rs1967309 (shown as a black circle …

Figure 4—figure supplement 3
Sex-specific long-range linkage disequilibrium in the Andean population (NAGD).

Genotype correlation between the loci identified in CETP in Figure 3a and all SNPs with MAF >5% in ADCY9 for the Andean population, in males (N = 54) and in females (N = 34). The horizontal line …

Figure 5 with 2 supplements
Effect of ADCY9 on CETP expression.

(a) Normalized expression of ADCY9 or CETP genes depending on wild type (WT) and ADCY9-KD in HepG2 cells from RNA sequencing on five biological replicates in each group. p-Values were obtained from …

Figure 5—source data 1

Normalized expression of ADCY9 and CETP genes HepG2 cells.

This file contains the normalized expression of ADCY9 (ENSG00000162104) and CETP (ENSG00000087237) for the WT (samples beginning by ‘Scr’) and ADCY9-KD (samples beginning by si-1039) in the HepG2 cell line. Each sample from the WT experiment is paired with the sample in the ADCY9-KD experiment finishing by the same number (from 1 to 5).

https://cdn.elifesciences.org/articles/69198/elife-69198-fig5-data1-v2.txt
Figure 5—source data 2

Residual of CETP expression by genotype.

This zip archive contains all files of CETP expression for correction of all covariables (Materials and methods) in the GEUVADIS (file beginning by F5b) and GTEx (Skin-male: file beginning by F5c; Artery-female: file beginning by F5d) datasets. The number of PEER factors added in the linear regression is written in the title of the file. In each file, the first column represents residual values of CETP expression after correcting for each covariable. The second column is the genotype of rs1967309 (0 = AA, 1 = AG, 2 = GG). The third column is the genotype combination of the rs1967309 (first number, same coding that the second column) and rs158477 (second number, 0 = GG, 1 = GA, 2 = AA).

https://cdn.elifesciences.org/articles/69198/elife-69198-fig5-data2-v2.zip
Figure 5—figure supplement 1
ADCY9/CETP interaction in HepG2 cells.

(a) Relative mRNA expression of CETP of HepG2 cells 72 hr post-transfection with siRNA against human ADCY9 (si1039). qPCR assay was normalized with PGK1 and HBS1L genes, n = 5 independent …

Figure 5—figure supplement 2
Interaction effect p-values on CETP expression depending by the number of PEER factors in Skin-sun exposed (a,b) and Tibial artery (c,d) in GTEx.

For the two-way interaction (rs1967309*rs158477) (a,c), rs158477 is codded as additive (GG = 0, GA = 1, AA = 2). In the additive model (green triangle), rs1967309 is codded as additive (AA = 0, AG = …

Figure 6 with 2 supplements
Epistatic association of rs1967309 and rs158477 on phenotypes in the UK biobank.

(a) Significance of the interaction effect between rs1967309 and rs158477 on several physiological traits, energy metabolism and cardiovascular outcomes overall and stratified by sex in the UK …

Figure 6—source data 1

Results of the interaction between rs1967309 and rs158477 on phenotypes in the UK biobank.

This file contains the results of the PheWAS for each phenotype in the Figure 6a for the sex-combined and stratified by sex analyses. p-Value are already converted to a -log10(p) scale and sorted by the most significant to the less significant results. Covariables used for the linear or logistic regressions are mentioned in Materials and methods. See Appendix 1—table 2 for the list of abbreviations.

https://cdn.elifesciences.org/articles/69198/elife-69198-fig6-data1-v2.txt
Figure 6—source data 2

Results for the cardiovascular phenotypes and biomarkers by sex and by rs1967309 genotypes in the UK biobank.

This zip archive contains the results for the cardiovascular phenotypes (file beginning by F6b) and biomarkers (file beginning by F6c) analyses. Those files contain the p-value, the estimate (AME) and standard error (SE, to multiply by 1.959964 to get the confidence interval for α = 0.05/2) of the association of rs158477 for each genotype of rs1967309 in male or female. The covariable used are mentioned in the Materials and methods. See Appendix 1—table 2 for the list of abbreviations.

https://cdn.elifesciences.org/articles/69198/elife-69198-fig6-data2-v2.zip
Figure 6—figure supplement 1
Single SNP effects of rs1967309 and rs158477 on phenotypes in the UK biobank.

Significance of the marginal effect of rs1967309 and rs158477, both codded as additive, on several physiological traits, energy metabolism and cardiovascular outcomes, overall and stratified by sex …

Figure 6—figure supplement 2
Epistatic association of rs1967309 and rs158477 on cardiovascular disease in GTEx.

(a) Effect of the rs158477 SNP on the cardiovascular phenotype (n = 693, cas = 120, control = 563) depending on the genotype of rs1967309 in GTEx. For both models, rs158477 was codded as additive …

Appendix 1—figure 1
Selection signature in ADCY9.

iHS values and recombination for all populations in the ADCY9 gene. Vertical black lines represent the highest recombination rates around rs1967309 from 1000G population-specific genetic maps. …

Appendix 1—figure 2
Population structure of Peruvian from LIMAA and Peruvian from 1000G.

Ancestry distribution on all chromosomes in the Peruvian from 1000G (a) and LIMAA cohort (b). Overall weighted proportion given by RFMix using reference populations from 1000G and Native American …

Appendix 1—figure 3
Populational differentiation of CETP gene using PBS statistic.

PBS values in the CETP gene, comparing the CHB (outgroup), MXL and PEL identified by different colors, overall (a), in males (b) and in females (c). Horizontal lines represent the 95th percentile …

Appendix 1—figure 4
Long-range linkage disequilibrium shown in CETP for the PEL population from 1000G, stratified by sex.

Genotype correlation (r2) between the three loci identified in CETP (see Figure 2a) to be higher than the 99th percentile and all SNPs with MAF >5% in ADCY9, in males (a) and females (b). The …

Appendix 1—figure 5
Long-range linkage disequilibrium in the Andean population from NAGD (a,b) and LIMAA cohort (c–f).

(a,b,d,f) Genotype correlation (r2) between rs1967309 and all SNPs with MAF >5% in CETP, for the Andean population from NAGD (a,b) and the LIMAA cohort (d,f). (c,e) Genotype correlation between the …

Appendix 1—figure 6
Significance of the correlation between ADCY9 and CETP expression across GTEx tissues.

P-values are presented on a -log10 scale and are obtained from a linear regression on normalized expression with correction for age, sex, top 5 PCs, ischemic time death, sequencing platform, and …

Appendix 1—figure 7
Epistatic effects between rs1967309 and rs158477 on CETP expression in GEUVADIS (LCL, N = 287) and CARTaGENE (Whole blood samples, N = 728).

P-values are presented on a -log10 scale and are reported in function of the number of PEER/sPEER factors in GEUVADIS (LCL) (a,c) and CARTaGENE (b,d) in sex-combined (a,b) and sex-stratified (c,d) …

Appendix 1—figure 8
Sex-combined epistatic effect p-values for the interaction between rs1967309 and rs158477 on CETP expression depending on the number of PEER factors in GTEx by tissue.

P-values are presented on a -log10 scale. For all models, rs158477 is coded as additive (GG = 0, GA = 1, AA = 2). In the additive model (green triangle), rs1967309 is coded as additive (AA = 0, AG = …

Appendix 1—figure 9
Sex-specific epistatic effects between rs1967309 and rs158477 on CETP expression depending on the number of sPEER factors in GTEx by tissue.

P-values are presented on a -log10 scale. For all models, rs158477 is coded as additive (GG = 0, GA = 1, AA = 2). In the additive model (green triangle), rs1967309 is coded as additive (AA = 0, AG = …

Appendix 1—figure 10
Population structure in datasets analysed.

We estimate population structure using UMAP on the top 10 PCs generated with flashPCA2 on (a) GTEx (N = 699) and (b) CARTaGENE (N = 12,056) biobanks. The self-reported white non-Latino individuals …

Author response image 1
Weir and Cockerham FST between males and females in PEL.

Horizontal line represents the 99th percentile value for this population (for chromosome 16).

Author response image 2
LRLD of rs1967309 with CETP gene and rs158477 in ADCY9 gene in UKB for SNPs with a MAF>5%.

The horizontal line is the 99th percentile of all pairs of SNPs between ADCY9 and CETP genes.

Author response image 3
Correlation between ADCY9 and CETP genes across tissues of GTEx.

(left) sex-combined, the shape represents the direction of the correlation. (right) Comparison of β of the correlation between both genes between male and female. Bars represent the standard error …

Author response image 4
Number of samples by genotype combination, in sex-combined and stratified by sex.
Author response image 5
Correlation between phenotypes in the UKB in sex-combined and stratified by sex.

Tables

Key resources table
Reagent type (species) or resourceDesignationSource or referenceIdentifiersAdditional information
Gene (Homo sapiens)CETPGenBankHGNC:1,869
Gene (Homo sapiens)ADCY9GenBankHGNC:240
Cell line (Homo sapiens)HepG2ATCCRRID:CVCL_0027Hepatoblastoma
Recombinant DNA reagentpEZ-M46-AC9 plasmidGeneCopoeiaEX-H0609-M46Methods section
Recombinant DNA reagentpEZ-M50-CETP plasmidGeneCopoeiaEX-C0070-M50Methods section
AntibodyAnti-CETP (rabbit monoclonal)Abcam#ab157183(1:1000) in 3 % BSA, TBS, tween 20 0.5%,
O/N 4 °C
AntibodyGoat anti-rabbit antibody (goat polyclonal)AbcamRRID:AB_955447(1:10 000)
in 3 % BSA
1 h at room
temperature
Sequence-based reagentHuman CETP_FIDT TechnologiesPCR primersCTACCTGT
CTTTCCATAA
Sequence-based reagentHuman CETP_RIDT TechnologiesPCR primersCATGATGT
TAGAGATGAC
Sequence-based reagentHuman ADCY9_FIDT TechnologiesPCR primersCTGAGGTT
CAAGAACATCC
Sequence-based reagentHuman ADCY9_RIDT TechnologiesPCR primersTGATTAATG
GGCGGCTTA
Sequence-based reagentSilencer Select siRNA against human ADCY9AmbionCat. #4390826 ID 1039CCUGAUGA
AAGAUUACUU
Utt
Sequence-based reagentSilencer Select siRNA against human CETPAmbionCat. #4392420 ID 2933GGACAGAUC
UGCAAAGAGAtt
Sequence-based reagentNegative Control siRNAAmbionCat. #4390844
Commercial assay or kitLipofectamine RNAiMAX reagentInvitrogenCat. #13,778
Commercial assay or kitLipofectamine 2000 reagentInvitrogenCat. #11668–019
Commercial assay or kitRNeasy Plus Mini KitQiagenCat. #74,136
Commercial assay or kitHigh-Capacity cDNA Reverse Transcription KitApplied BiosystemsCat. #4368814
Commercial assay or kitAgilent RNA 6000 Nano Kit for Bioanalyzer 2,100 SystemAgilent TechnologiesCat. #5067–1511
Commercial assay or kitSYBR-Green reaction mixBioRadCat. #1725274
Commercial assay or kitAmicon Ultra 0.5 ml 10 kDa cutoff unitsMillipore SigmaCat. #UFC501096
Commercial assay or kitWestern Lightning ECL ProPerkin ElmerCat. #NEL122001EA
Commercial assay or kitTGX Stain-Free FastCast Acrylamide 10%BioRadCat# 1610183
Software, algorithmTrimGalore!DOI:10.14806/ej.17.1.200RRID:SCR_011847
Software, algorithmSTAR (v.2.6.1a)DOI:10.1093/bioinformatics/bts635RRID:SCR_019993
Software, algorithmRSEM (v.1.3.1)DOI:10.1186/1471-2105-12-323RRID:SCR_013027
Software, algorithmR statistical software (v.3.6.0/v.3.6.1)https://www.r-project.org/RRID:SCR_001905
Software, algorithmFlashPCA2DOI:10.1093/bioinformatics/btx299RRID:SCR_021680
Software, algorithmVcftools (v.0.1.17)DOI:10.1093/bioinformatics/btr330RRID:SCR_001235
Software, algorithmRFMix (v.2.03)DOI:10.1016 /j.ajhg.2013.06.020
Software, algorithmPEERDOI:10.1038/nprot.2011.457RRID:SCR_009326
Software, algorithmpyGenClean (v.1.8.3)DOI:10.1093/bioinformatics/btt261
Software, algorithmSAS (v.9.4)https://www.sas.com/en_us/software/stat.htmlRRID:SCR_008567
Software, algorithmEPO pipeline (version e59)DOI:10.1093/database/bav096
Software, algorithmBcftools (v.1.9)DOI:10.1093/bioinformatics/btr509RRID:SCR_005227
Software, algorithmGenotype
Harmonizer (v.1.4.20)
DOI:10.1186/1756-0500-7-901
Software, algorithmHapbin (v.1.3.0)DOI:10.1093/molbev/msv172
Software, algorithmSHAPEIT2 (r.837)DOI:10.1038/nmeth.1785
Software, algorithmPBWTDOI:10.1093/bioinformatics/btu014
Software, algorithmBeacon designer software (v.8) (Premier Biosoft)http://www.premierbiosoft.com/qOligo/Oligo.jsp?PID=1
Other1000 Genomes projectDOI:10.1038/nature15393RRID:SCR_006828
OtherLIMAADOI:10.1038 /s41467-019-11664-1dbGAP:phs002025.
v1.p1
dbgap project #26,882
OtherNative American genetic datasetDOI:10.1038/nature11258
OtherGEUVADISDOI:10.1038/nature12531RRID:SCR_000684
OtherGTEx (v8)DOI:10.1038 /ng.2653RRID:SCR_013042dbgap project #19,088
OtherCARTaGENE biobankDOI:10.1093/ije/dys160RRID:SCR_010614CAG project number 406,713
OtherUK biobankDOI:10.1371/journal.pmed.1001779RRID:SCR_012815UKB project #15,357 and #20,168
OtherSanger Imputation ServerDOI:10.3389/fgene.2019.00034
Table 1
Cohort information.

Sample sizes are reported after quality control steps.

Cohort/SubpopulationAbbreviationEthnicitySample size(% female)AgeReference
1000 G – PeruvianPEL*Peruvian85 (52%)NAAuton et al., 2015
LIMAA/PeruvianLIMAAPeruvian3,243 (40%)29.6 ± 13.8Asgari et al., 2020; Luo et al., 2019
Native Amerind/AndeanNAGD/ANDAmerind/Peruvian88 (40%)NAReich et al., 2012
GEUVADISGEUVADIS*European descent287 (54%)NALappalainen et al., 2013
CARTaGENECaGEuropean descent728 (51%)53.6 ± 8.7Awadalla et al., 2013
GTExGTExEuropean descent699 (34%)52.6 ± 13.1GTEx Consortium, 2013
UK biobankUkb*European descent413,138 (54%)56.8 ± 8.0Sudlow et al., 2015
  1. *

    indicates a discovery cohort.

  2. NA: not available.

Appendix 1—table 1
Long-range linkage disequilibrium analysis in three datasets, and in subsets of the cohorts.

Number of individuals (N) in each subset is reported. P-values correspond to the ADCY9/CETP empirical p-values computed as described in Section Long-range linkage disequilibrium in Methods. r2 were …

CohortPopulationSexNumberr2p-value ADCY9-CETP
1000GYRIAll1080.02360.11
CEUAll990.00030.86
GBRAll910.01170.28
CHBAll1030.0040.53
MXLAll640.00070.83
PEL*All850.07965.42 × 10–3
Male410.34838.23 × 10–5
Female440.00160.78
LIMAALIMAAAll3,2430.00463.24 × 10–3
Male19410.00973.71 × 10–3
Female1,3020.00030.52
NAGDNorthern Amerind(NOA)All810.00840.44
Male270.06340.16
Female540.06990.07
Central Amerind(CEA)All810.02810.12
Male340.03160.28
Female470.02570.24
Andean(AND)All880.02930.04
Male540.04360.09
Female340.01250.55
  1. *

    Discovery cohort.

Appendix 1—table 2
Details on metabolic and clinical variables extracted from the UK Biobank.
Variable IDUK biobank variable locationNumber of samples used for interaction
Category 100011 - Blood pressure - Physical measures - UK Biobank Assessment Centre
Pulse rate at baseline(Pulse rate)Units: bpmData-Field 102 (automatic entry) or Data-Field 95 (manual entry), to be derived as follows:
  • Pulse rate, automated reading (Data-Field 102) used mean of available measures for instance 0 (baseline) only. If a manual measure is available for an individual (Data Field 95 below) then do not use this automated reading (assumed to be abnormal).

  • Pulse rate (during blood-pressure measurement) (Data-Field 95), use Instance 0 (baseline). Use mean when there are multiple measures for a same individual.

All = 395,319Male = 182,279Female = 213,040
Diastolic blood pressure at baseline(Diastolic BP)Units: mmHgData-Field 4,079 (automatic entry) or Data-Field 94 (manual entry), as follow:
  • Diastolic blood pressure, automated reading: Data-Field 4079,, use mean of available measures for instance 0 (baseline) only. If a manual measure is available for an individual (Data Field 94) then do not use this automated reading (assumed to be abnormal).

  • Diastolic blood pressure, manual reading: Data-Field 94, use mean of available measures for instance 0 (baseline) only.

All = 395,384Male = 182,326Female = 213,058
Systolic blood pressure at baseline(Systolic BP)Units: mmHgData-Field 4,080 (automatic entry) or Data-Field 93 (manual entry), as follow:
  1. Systolic blood pressure, automated reading: Data-Field 4080,, use mean of available measures for instance 0 (baseline) only. If a manual measure is available for an individual (Data Field 93) then do not use this automated reading (assumed to be abnormal).

  2. Systolic blood pressure, manual reading: Data-Field 93, use mean of available measures for instance 0 (baseline) only.

All = 395,353Male = 182,316Female = 213,037
Category 100010 - Body size measures - Anthropometry - Physical measures - UK Biobank Assessment Centre
Waist circumference at baseline (Waist circumference)Units: cmData field 48, use mean of available measures for instance 0 (baseline) only.All = 395,006Male = 182,089Female = 212,917
Hip circumference at baseline (Hip circumference)Units: cmData field 49, use mean of available measures for instance 0 (baseline) only.All = 394,651Male = 181,988Female = 212,663
Waist-hip ratioCompute waist/hipAll = 394,944Male = 182,056Female = 212,888
WeightUnits: KgData-Field 21,002 (automatic entry) or Data-Field 3,160 (manual entry), as follow:(3) Weight: Data-Field 21002,, use mean of available measures for instance 0 (baseline) only.Only if unavailable, then use:(4) Weight, manual reading: Data-Field 3160,, use mean of available measures for instance 0 (baseline) only.All = 394,377Male = 181,732Female = 212,645
HeightUnits: cmData-Field 50 or 12,144.(5) Standing height: Data Field 50, used mean of available measures for instance 0 (baseline) only.Only if unavailable, then use:(6) Height: Data-Field 12144,, used mean of available measures, as this is a singular instance fieldAll = 394,871Male = 181,969Female = 212,902
UK Biobank BMI(BMI)Units: Kg/m2Data field 21001,, used mean of available measures for instance 0 (baseline) only.All = 394,173Male = 181,705Female = 212,468
Category 100009 - Impedance measures - Anthropometry - Physical measures - UK Biobank Assessment Centre
Trunk fat percentage(% Trunk fat)Units: %Data field 23127,, use mean of available measures for instance 0 (baseline) only.All = 388,569Male = 178,837Female = 209,732
Body fat percentage(% Body fat)Units: %Data field 23099,, use mean of available measures for instance 0 (baseline) only.All = 388,600Male = 178,752Female = 209,848
Basal metabolic rateUnits: KJData field 23105,, use mean of available measures for instance 0 (baseline) only.All = 388,585Male = 178,758Female = 209,827
Whole body water massUnites: KgData field 23102,, use mean of available measures for instance 0 (baseline) only.All = 388,719Male = 178,881Female = 209.838
Category 100020 - Spirometry - Physical measures - UK Biobank Assessment Centre
Forced vital capacity(FVC)Units: LData field 20151,, use mean if more than one measure.All = 297,461Male = 138,909Female = 158,552
Forced expiratory volume in 1 second(FEV1)Units: LData field 20150,, use mean if more than one measure.All = 297,499Male = 138,937Female = 158,562
Category 100057 - Sleep - Lifestyle and environment - Touchscreen - UK Biobank Assessment Centre
Sleep durationUnits: hours/dayData field 1160,, use mean of available measures for instance 0 (baseline) only.All = 393,133Male = 181,452Female = 211,681
Category 100072 - Early life factors - Verbal interview - UK Biobank Assessment Centre
Birth weightUnits: KgData field 20022,, use mean if more than one measure.All = 227,244Male = 89,715Female = 137,529
Category 717 - Biomarkers
Apolipoprotein A1(ApoA)Units: g/LData field 30630, use mean of available measures for instance 0 (baseline) only.Standardized using the mean: (x-mean)/sdAll = 413,138Male = 190,454Female = 222,684
High Density Lipoprotein(HDL-c)Units: mmol/LData field 30760, use mean of available measures for instance 0 (baseline) only.Standardized using the mean: (x-mean)/sd
Lipoprotein (a)(Lp(a))Units: nmol/LData field 30780, use mean of available measures for instance 0 (baseline) only.Standardized using the mean: (x-mean)/sd
C-Reactive Protein(CRP)Units: mmol/LData field 30710, use mean of available measures for instance 0 (baseline) only.Ln transformation, then standardized using the mean: (x-mean)/sd
Low Density Lipoprotein(LDL-c)Units: mmol/LData field 30790, use mean of available measures for instance 0 (baseline) only.Standardized using the mean: (x-mean)/sd
Apolipoprotein B(ApoB)Units: g/LData field 30640, use mean of available measures for instance 0 (baseline) only.Standardized using the mean: (x-mean)/sd
Category of operation procedure codes (OPCS) and hospitalization or death record codes(ICD9/ICD10)
Coronary artery disease(CAD)Prevalent or incident(cases/controls)All = 413,138 (44,713/368,425)Male = 190,454 (29,910/160,544)Female = 222,684 (14,803/207,881)
Myocardial Infarction(MI)Prevalent or incident(cases/controls)All = 413,138 (18,559/394,579)Male = 190,454 (13,812/176,642)Female = 222,684 (4,747/217,937)
Appendix 1—table 3
Primers sequence for real-time PCR quantification in HepG2 cells for the KD-ADCY9 and KD-CETP experimentations.
SpeciesGeneStrainSequence
HumanADCY9Forward5’ CTGAGGTTCAAGAACATCC 3’
Reverse5’ TGATTAATGGGCGGCTTA 3’
CETPForward5’ CTACCTGTCTTTCCATAA 3’
Reverse5’ CATGATGTTAGAGATGAC 3’
HBS1LForward5’ ACAAGAATGAGGCAACAG 3’
Reverse5’ AGATACTCCAGGCACTTC 3’
PGK1Forward5’ GTGGAGGAAGAAGGGAAG 3’
Reverse5’ AAGCATCATTGACATAGACAT 3’
Author response table 1
OrganSexNumber of samples
Brain-AmygdalaFemale34
Brain-Anterior Cingulate Cortex (BA24)Female39
Brain-Caudate basal gangliaFemale45
Brain-Cerebellar HemisphereFemale46
Brain-Frontal Cortex (BA9)Female44
Brain-HippocampusFemale45
Brain-HypothalamusFemale44
Brain-Nucleus accumbens basal gangliaFemale49
Brain-Putamen (basal ganglia)Female38
Brain-Spinal cord cervical c-1Female42
Brain-Substantia nigraFemale28
Cells-EBV-transformed lymphocytesFemale43
Kidney-CortexMale/Female48/17
Minor Salivary GlandFemale32
Author response table 2
DatabaseSNP - VariantTOPMED imputationSanger Imputation Server - Haplotype Reference Consortium (in manuscript)
LIMAArs1967309 A77%76%
rs158477 G79%79%
NAGD-Andeanrs1967309 A77%77%
rs158477 G74%73%
Author response table 3
AllMaleFemale
rs1967309-A0.3928180.3929350.392719
rs158477-G0.4716280.4717970.471484

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