Summary

Summary {data-width=650}

Manhattan plot

manhattan_plot

QQ plot

qq_plot

AF plot

af_plot

P-Z plot

pz_plot

beta_std plot

beta_std_plot

Metadata

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}
 

LDSC

*********************************************************************
* LD Score Regression (LDSC)
* Version 1.0.1
* (C) 2014-2019 Brendan Bulik-Sullivan and Hilary Finucane
* Broad Institute of MIT and Harvard / MIT Department of Mathematics
* GNU General Public License v3
*********************************************************************
Call: 
./ldsc.py \
--h2 /data/cromwell-executions/qc/2e0cd451-340d-42f2-a7b8-53aafe5542a4/call-ldsc/inputs/268670742/ieu-b-103.vcf.gz \
--ref-ld-chr /data/ref/eur_w_ld_chr/ \
--out /data/igd/ieu-b-103/ldsc.txt \
--w-ld-chr /data/ref/eur_w_ld_chr/ 

Beginning analysis at Fri Mar 19 13:11:57 2021
Reading summary statistics from /data/cromwell-executions/qc/2e0cd451-340d-42f2-a7b8-53aafe5542a4/call-ldsc/inputs/268670742/ieu-b-103.vcf.gz ...
Read summary statistics for 2529804 SNPs.
Dropped 864 SNPs with duplicated rs numbers.
Reading reference panel LD Score from /data/ref/eur_w_ld_chr/[1-22] ... (ldscore_fromlist)
Read reference panel LD Scores for 1290028 SNPs.
Removing partitioned LD Scores with zero variance.
Reading regression weight LD Score from /data/ref/eur_w_ld_chr/[1-22] ... (ldscore_fromlist)
Read regression weight LD Scores for 1290028 SNPs.
After merging with reference panel LD, 1150402 SNPs remain.
After merging with regression SNP LD, 1150402 SNPs remain.
Using two-step estimator with cutoff at 30.
Total Observed scale h2: 0.0612 (0.0109)
Lambda GC: 1.0336
Mean Chi^2: 1.0547
Intercept: 1.0001 (0.0069)
Ratio: 0.0012 (0.1254)
Analysis finished at Fri Mar 19 13:12:53 2021
Total time elapsed: 56.73s

QC metrics

Metrics

Metrics

{
    "af_correlation": "NA",
    "inflation_factor": 1.0426,
    "mean_EFFECT": 0.0001,
    "n": 46368,
    "n_snps": 2529804,
    "n_clumped_hits": 11,
    "n_p_sig": 188,
    "n_mono": 0,
    "n_ns": 0,
    "n_mac": 0,
    "is_snpid_unique": true,
    "n_miss_EFFECT": 0,
    "n_miss_SE": 0,
    "n_miss_PVAL": 0,
    "n_miss_AF": 2529804,
    "n_miss_AF_reference": 22414,
    "n_est": "NA",
    "ratio_se_n": "NA",
    "mean_diff": "NaN",
    "ratio_diff": "NaN",
    "sd_y_est1": "NA",
    "sd_y_est2": "NA",
    "r2_sum1": 0,
    "r2_sum2": 0,
    "r2_sum3": 0,
    "r2_sum4": 0,
    "ldsc_nsnp_merge_refpanel_ld": 1150402,
    "ldsc_nsnp_merge_regression_ld": 1150402,
    "ldsc_observed_scale_h2_beta": 0.0612,
    "ldsc_observed_scale_h2_se": 0.0109,
    "ldsc_intercept_beta": 1.0001,
    "ldsc_intercept_se": 0.0069,
    "ldsc_lambda_gc": 1.0336,
    "ldsc_mean_chisq": 1.0547,
    "ldsc_ratio": 0.0018
}
 

Flags

name value
af_correlation NA
inflation_factor FALSE
n FALSE
is_snpid_non_unique FALSE
mean_EFFECT_nonfinite FALSE
mean_EFFECT_05 FALSE
mean_EFFECT_01 FALSE
mean_chisq FALSE
n_p_sig FALSE
miss_EFFECT FALSE
miss_SE FALSE
miss_PVAL FALSE
ldsc_ratio FALSE
ldsc_intercept_beta FALSE
n_clumped_hits FALSE
r2_sum1 FALSE
r2_sum2 FALSE
r2_sum3 FALSE
r2_sum4 FALSE

Definitions

General metrics

  • af_correlation: Correlation coefficient between AF and AF_reference.
  • inflation_factor (lambda): Genomic inflation factor.
  • mean_EFFECT: Mean of EFFECT size.
  • n: Maximum value of reported sample size across all SNPs, \(n\).
  • n_clumped_hits: Number of clumped hits.
  • n_snps: Number of SNPs
  • n_p_sig: Number of SNPs with pvalue below 5e-8.
  • n_mono: Number of monomorphic (MAF == 1 or MAF == 0) SNPs.
  • n_ns: Number of SNPs with nonsense values:
    • alleles other than A, C, G or T.
    • P-values < 0 or > 1.
    • negative or infinite standard errors (<= 0 or = Infinity).
    • infinite beta estimates or allele frequencies < 0 or > 1.
  • n_mac: Number of cases where MAC (\(2 \times N \times MAF\)) is less than 6.
  • is_snpid_unique: true if the combination of ID REF ALT is unique and therefore no duplication in snpid.
  • n_miss_<*>: Number of NA observations for <*> column.

se_n metrics

  • n_est: Estimated sample size value, \(\widehat{n}\).
  • ratio_se_n: \(\texttt{ratio_se_n} = \frac{\sqrt{\widehat{n}}}{\sqrt{n}}\). We expect ratio_se_n to be 1. When it is not 1, it implies that the trait did not have a variance of 1, the reported sample size is wrong, or that the SNP-level effective sample sizes differ markedly from the reported sample size.
  • mean_diff: \(\texttt{mean_diff} = \sum_{j} \frac{\widehat{\beta_j^{std}} - \beta_j}{\texttt{n_snps}}\), mean difference between the standardised beta, predicted from P-values, and the observed beta. The difference should be very close to zero if trait has a variance of 1.
    • \(\widehat{\beta_j^{std}} = \sqrt{\frac{{z}_j^2 / ({z}_j^2 + n -2)}{2 \times {MAF}_j \times (1 - {MAF}_j)}} \times sign({z}_j)\),
    • \({z}_j = \frac{\beta_j}{{se}_j}\),
    • and \(\beta_j\) is the reported effect size.
  • ratio_diff: \(\texttt{ratio_diff} = |\frac{\texttt{mean_diff}}{\texttt{mean_diff2}}|\), absolute ratio between the mean of diff and the mean of diff2 (expected difference between the standardised beta predicted from P-values, and the standardised beta derived from the observed beta divided by the predicted SD; NOT reported). The ratio should be close to 1. If different from 1, then implies that the betas are not in a standard deviation scale.
    • \(\texttt{mean_diff2} = \sum_{j} \frac{\widehat{\beta_j^{std}} - \beta^{\prime}_j}{\texttt{n_snps}}\)
    • \(\beta^{\prime}_j = \frac{\beta_j}{\widehat{\texttt{sd2}}_{y}}\)
  • sd_y_est1: The standard deviation for the trait inferred from the reported sample size, median standard errors for the SNP-trait assocations and SNP variances.
    • \(\widehat{\texttt{sd1}}_{y} = \frac{\sqrt{n} \times median({se}_j)}{C}\),
    • \(C = median(\frac{1}{\sqrt{2 \times {MAF}_j \times (1 - {MAF}_j)}})\),
    • and \({se}_j\) is the reported standard error.
  • sd_y_est2: The standard deviation for the trait inferred from the reported sample size, Z statistics for the SNP-trait effects (beta/se) and allele frequency.
    • \(\widehat{\texttt{sd2}}_{y} = median(\widehat{sd_j})\),
    • \(\widehat{sd_j} = \frac{\beta_j}{\widehat{\beta_j^{std}}}\),

r2 metrics

Sum of variance explained, calculated from the clumped top hits sample.

  • r2_sum<*>: r2 statistics under various assumptions
    • 1: \(r^2 = \sum_j{\frac{2 \times \beta_j^2 \times {MAF}_j \times (1 - {MAF}_j)}{\texttt{var1}}}\), \(\texttt{var1} = 1\).
    • 2: \(r^2 = \sum_j{\frac{2 \times \beta_j^2 \times {MAF}_j \times (1 - {MAF}_j)}{\texttt{var2}}}\), \(\texttt{var2} = {\widehat{\texttt{sd1}}_{y}}^2\),
    • 3: \(r^2 = \sum_j{\frac{2 \times \beta_j^2 \times {MAF}_j \times (1 - {MAF}_j)}{\texttt{var3}}}\), \(\texttt{var3} = {\widehat{\texttt{sd2}}_{y}}^2\),
    • 4: \(r^2 = \sum_j{\frac{F_j}{F_j + n - 2}}\), \(F = \frac{\beta_j^2}{{se}_j^2}\).

LDSC metrics

Metrics from LD regression

  • ldsc_nsnp_merge_refpanel_ld: Number of remaining SNPs after merging with reference panel LD.
  • ldsc_nsnp_merge_regression_ld: Number of remaining SNPs after merging with regression SNP LD.
  • ldsc_observed_scale_h2_{beta,se} Coefficient value and SE for total observed scale h2.
  • ldsc_intercept_{beta,se}: Coefficient value and SE for intercept. Intercept is expected to be 1.
  • ldsc_lambda_gc: Lambda GC statistics.
  • ldsc_mean_chisq: Mean \(\chi^2\) statistics.
  • ldsc_ratio: \(\frac{\texttt{ldsc_intercept_beta} - 1}{\texttt{ldsc_mean_chisq} - 1}\), the proportion of the inflation in the mean \(\chi^2\) that the LD Score regression intercepts ascribes to causes other than polygenic heritability. The value of ratio should be close to zero, though in practice values of 0.1-0.2 are not uncommon, probably due to sample/reference LD Score mismatch or model misspecification (e.g., low LD variants have slightly higher \(h^2\) per SNP).

Flags

When a metric needs attention, the flag should return TRUE.

  • af_correlation: abs(af_correlation) < 0.7.
  • inflation_factor: inflation_factor > 1.2.
  • n: n (max reported sample size) < 10000.
  • is_snpid_non_unique: NOT is_snpid_unique.
  • mean_EFFECT_nonfinite: mean(EFFECT) is NA, NaN, or Inf.
  • mean_EFFECT_05: abs(mean(EFFECT)) > 0.5.
  • mean_EFFECT_01: abs(mean(EFFECT)) > 0.1.
  • mean_chisq: ldsc_mean_chisq > 1.3 or ldsc_mean_chisq < 0.7.
  • n_p_sig: n_p_sig > 1000.
  • miss_<*>: n_miss_<*> / n_snps > 0.01.
  • ldsc_ratio: ldsc_ratio > 0.5
  • ldsc_intercept_beta: ldsc_intercept_beta > 1.5
  • n_clumped_hits: n_clumped_hits > 1000
  • r2_sum<*>: r2_sum<*> > 0.5

Plots

  • Manhattan plot
    • Red line: \(-log_{10}^{5 \times 10^{-8}}\)
    • Blue line: \(-log_{10}^{5 \times 10^{-5}}\)
  • QQ plot
  • AF plot
  • P-Z plot
  • beta_std plot: Scatter plot between \(\widehat{\beta_j^{std}}\) and \(\beta_j\)

Diagnostics

Details

Summary stats

skim_type skim_variable n_missing complete_rate character.min character.max character.empty character.n_unique character.whitespace logical.mean logical.count numeric.mean numeric.sd numeric.p0 numeric.p25 numeric.p50 numeric.p75 numeric.p100 numeric.hist
character ID 0 1.00000 3 42 0 2529799 0 NA NA NA NA NA NA NA NA NA NA
character REF 0 1.00000 1 1 0 4 0 NA NA NA NA NA NA NA NA NA NA
character ALT 0 1.00000 1 1 0 4 0 NA NA NA NA NA NA NA NA NA NA
logical AF 2529804 0.00000 NA NA NA NA NA NaN : NA NA NA NA NA NA NA NA
numeric CHROM 0 1.00000 NA NA NA NA NA NA NA 8.595755e+00 5.669368e+00 1.0000 4.000000e+00 8.000000e+00 1.200000e+01 2.30000e+01 ▇▅▅▂▂
numeric POS 0 1.00000 NA NA NA NA NA NA NA 7.886410e+07 5.579983e+07 6888.0000 3.255575e+07 7.020820e+07 1.144403e+08 2.49219e+08 ▇▆▅▂▁
numeric EFFECT 0 1.00000 NA NA NA NA NA NA NA 6.780000e-05 7.151900e-03 -0.1892 -3.300000e-03 0.000000e+00 3.400000e-03 1.96700e-01 ▁▁▇▁▁
numeric SE 0 1.00000 NA NA NA NA NA NA NA 5.795700e-03 4.078500e-03 0.0031 3.700000e-03 4.400000e-03 6.200000e-03 8.44000e-02 ▇▁▁▁▁
numeric PVAL 0 1.00000 NA NA NA NA NA NA NA 4.932469e-01 2.909962e-01 0.0000 2.398999e-01 4.909994e-01 7.456002e-01 1.00000e+00 ▇▇▇▇▇
numeric PVAL_ztest 0 1.00000 NA NA NA NA NA NA NA 4.932541e-01 2.910497e-01 0.0000 2.399947e-01 4.917677e-01 7.456925e-01 1.00000e+00 ▇▇▇▇▇
numeric AF_reference 22414 0.99114 NA NA NA NA NA NA NA 3.618150e-01 2.559484e-01 0.0000 1.465650e-01 3.003190e-01 5.465260e-01 1.00000e+00 ▇▆▃▃▂
numeric N 0 1.00000 NA NA NA NA NA NA NA 4.636800e+04 0.000000e+00 46368.0000 4.636800e+04 4.636800e+04 4.636800e+04 4.63680e+04 ▁▁▇▁▁

Head and tail

CHROM POS ID REF ALT EFFECT SE PVAL PVAL_ztest AF AF_reference N
1 721290 rs12565286 G C -0.0007 0.0111 0.9488001 0.9497163 NA 0.0371406 46368
1 723819 rs11804171 T A -0.0015 0.0111 0.8922000 0.8925050 NA 0.1345850 46368
1 723891 rs2977670 G C -0.0076 0.0208 0.7148008 0.7148243 NA 0.7799520 46368
1 750235 rs12138618 G A -0.0077 0.0204 0.7066006 0.7058385 NA NA 46368
1 752566 rs3094315 G A 0.0037 0.0049 0.4495997 0.4501878 NA 0.7182510 46368
1 754192 rs3131968 A G 0.0121 0.0104 0.2451997 0.2446423 NA 0.6785140 46368
1 768448 rs12562034 G A 0.0032 0.0102 0.7565001 0.7537295 NA 0.1918930 46368
1 775659 rs2905035 A G 0.0106 0.0055 0.0533495 0.0539457 NA 0.7450080 46368
1 777122 rs2980319 A T 0.0109 0.0055 0.0473904 0.0474996 NA 0.7472040 46368
1 779322 rs4040617 A G -0.0106 0.0055 0.0548504 0.0539457 NA 0.2264380 46368
CHROM POS ID REF ALT EFFECT SE PVAL PVAL_ztest AF AF_reference N
22 51216564 rs9616970 T C -0.0003 0.0075 0.9687000 0.9680931 NA 0.1563500 46368
22 51217134 rs117417021 A G -0.0034 0.0054 0.5274994 0.5289369 NA 0.2671730 46368
22 51222100 rs114553188 G T -0.0040 0.0096 0.6761997 0.6769222 NA 0.0880591 46368
22 51223637 rs375798137 G A -0.0028 0.0096 0.7737007 0.7705415 NA 0.0788738 46368
22 51229805 rs9616985 T C 0.0076 0.0103 0.4641999 0.4605971 NA 0.0730831 46368
23 35921591 rs2204667 C G -0.0029 0.0046 0.5290004 0.5284102 NA NA 46368
23 51666786 rs14115 A G 0.0101 0.0075 0.1750000 0.1780876 NA NA 46368
23 70163799 rs1626496 A C -0.0108 0.0067 0.1080001 0.1069749 NA NA 46368
23 91415872 rs6562597 G A 0.0104 0.0125 0.4039001 0.4054089 NA 0.0021192 46368
23 118495837 rs12882977 G A -0.0003 0.0034 0.9243001 0.9296897 NA 0.2307280 46368

bcf preview

1   721290  rs12565286  G   C   .   PASS    .   ES:SE:LP:SS:ID  -0.0007:0.0111:0.0228253:46368:rs12565286
1   723819  rs11804171  T   A   .   PASS    .   ES:SE:LP:SS:ID  -0.0015:0.0111:0.0495378:46368:rs11804171
1   723891  rs2977670   G   C   .   PASS    .   ES:SE:LP:SS:ID  -0.0076:0.0208:0.145815:46368:rs2977670
1   750235  rs12138618  G   A   .   PASS    .   ES:SE:LP:SS:ID  -0.0077:0.0204:0.150826:46368:rs12138618
1   752566  rs3094315   G   A   .   PASS    .   ES:SE:LP:SS:ID  0.0037:0.0049:0.347174:46368:rs3094315
1   754192  rs3131968   A   G   .   PASS    .   ES:SE:LP:SS:ID  0.0121:0.0104:0.61048:46368:rs3131968
1   768448  rs12562034  G   A   .   PASS    .   ES:SE:LP:SS:ID  0.0032:0.0102:0.121191:46368:rs12562034
1   775659  rs2905035   A   G   .   PASS    .   ES:SE:LP:SS:ID  0.0106:0.0055:1.27287:46368:rs2905035
1   777122  rs2980319   A   T   .   PASS    .   ES:SE:LP:SS:ID  0.0109:0.0055:1.32431:46368:rs2980319
1   779322  rs4040617   A   G   .   PASS    .   ES:SE:LP:SS:ID  -0.0106:0.0055:1.26082:46368:rs4040617
1   780785  rs2977612   T   A   .   PASS    .   ES:SE:LP:SS:ID  0.0104:0.0055:1.2327:46368:rs2977612
1   785050  rs2905062   G   A   .   PASS    .   ES:SE:LP:SS:ID  0.0096:0.0055:1.09637:46368:rs2905062
1   785989  rs2980300   T   C   .   PASS    .   ES:SE:LP:SS:ID  0.0076:0.0054:0.797512:46368:rs2980300
1   798026  rs4951864   C   T   .   PASS    .   ES:SE:LP:SS:ID  -0.0043:0.0103:0.16877:46368:rs4951864
1   798801  rs12132517  G   A   .   PASS    .   ES:SE:LP:SS:ID  0.0039:0.0103:0.153354:46368:rs12132517
1   798959  rs11240777  G   A   .   PASS    .   ES:SE:LP:SS:ID  -0.0071:0.0059:0.641494:46368:rs11240777
1   947034  rs2465126   G   A   .   PASS    .   ES:SE:LP:SS:ID  -0.0306:0.0241:0.69229:46368:rs2465126
1   949608  rs1921  G   A   .   PASS    .   ES:SE:LP:SS:ID  -0.0053:0.0091:0.250496:46368:rs1921
1   957898  rs2799064   G   T   .   PASS    .   ES:SE:LP:SS:ID  -0.0047:0.0093:0.211902:46368:rs2799064
1   962210  rs3128126   A   G   .   PASS    .   ES:SE:LP:SS:ID  -0.0019:0.0091:0.0799289:46368:rs3128126
1   990380  rs3121561   C   T   .   PASS    .   ES:SE:LP:SS:ID  -0.008:0.008:0.505289:46368:rs3121561
1   998501  rs3813193   G   C   .   PASS    .   ES:SE:LP:SS:ID  -0.0016:0.0097:0.0629337:46368:rs3813193
1   1003629 rs4075116   C   T   .   PASS    .   ES:SE:LP:SS:ID  0.002:0.0046:0.175159:46368:rs4075116
1   1005806 rs3934834   C   T   .   PASS    .   ES:SE:LP:SS:ID  -0.0006:0.008:0.0247061:46368:rs3934834
1   1017170 rs3766193   C   G   .   PASS    .   ES:SE:LP:SS:ID  0.0017:0.0041:0.168706:46368:rs3766193
1   1017197 rs3766192   C   T   .   PASS    .   ES:SE:LP:SS:ID  0.0014:0.0042:0.128485:46368:rs3766192
1   1017587 rs3766191   C   T   .   PASS    .   ES:SE:LP:SS:ID  0.0007:0.0084:0.032031:46368:rs3766191
1   1018562 rs9442371   C   T   .   PASS    .   ES:SE:LP:SS:ID  0.0012:0.0041:0.119015:46368:rs9442371
1   1018704 rs9442372   A   G   .   PASS    .   ES:SE:LP:SS:ID  0.0015:0.0039:0.157703:46368:rs9442372
1   1021346 rs10907177  A   G   .   PASS    .   ES:SE:LP:SS:ID  -0.0057:0.0097:0.252122:46368:rs10907177
1   1021415 rs386627436 A   G   .   PASS    .   ES:SE:LP:SS:ID  0.0014:0.0048:0.111035:46368:rs386627436
1   1021583 rs10907178  A   C   .   PASS    .   ES:SE:LP:SS:ID  -0.0048:0.0098:0.202871:46368:rs10907178
1   1021695 rs9442398   A   G   .   PASS    .   ES:SE:LP:SS:ID  0.002:0.0048:0.16877:46368:rs9442398
1   1022037 rs6701114   C   T   .   PASS    .   ES:SE:LP:SS:ID  0.0029:0.0051:0.24382:46368:rs6701114
1   1025301 rs9442400   T   C   .   PASS    .   ES:SE:LP:SS:ID  0.0043:0.0379:0.0414839:46368:rs9442400
1   1026707 rs4074137   C   A   .   PASS    .   ES:SE:LP:SS:ID  0.0091:0.0075:0.637895:46368:rs4074137
1   1030565 rs6687776   C   T   .   PASS    .   ES:SE:LP:SS:ID  -0.0042:0.0081:0.221487:46368:rs6687776
1   1030633 rs6678318   G   A   .   PASS    .   ES:SE:LP:SS:ID  0.017:0.012:0.801893:46368:rs6678318
1   1031540 rs776599533 A   G   .   PASS    .   ES:SE:LP:SS:ID  0.0098:0.0078:0.669586:46368:rs776599533
1   1036959 rs1162868282    T   C   .   PASS    .   ES:SE:LP:SS:ID  0.0037:0.0087:0.176852:46368:rs1162868282
1   1039098 rs11260595  C   A   .   PASS    .   ES:SE:LP:SS:ID  0.0107:0.0273:0.158641:46368:rs11260595
1   1040026 rs6671356   T   C   .   PASS    .   ES:SE:LP:SS:ID  -0.0002:0.0086:0.00952795:46368:rs6671356
1   1041700 rs6604968   A   G   .   PASS    .   ES:SE:LP:SS:ID  0.0086:0.012:0.323672:46368:rs6604968
1   1046164 rs386627439 C   T   .   PASS    .   ES:SE:LP:SS:ID  0.0036:0.008:0.182831:46368:rs386627439
1   1048955 rs4970405   A   G   .   PASS    .   ES:SE:LP:SS:ID  0.0062:0.0081:0.350568:46368:rs4970405
1   1049950 rs12726255  A   G   .   PASS    .   ES:SE:LP:SS:ID  -0.0002:0.0076:0.0105947:46368:rs12726255
1   1053452 rs4970409   G   A   .   PASS    .   ES:SE:LP:SS:ID  0.0062:0.0087:0.326979:46368:rs4970409
1   1060235 rs7540009   G   A   .   PASS    .   ES:SE:LP:SS:ID  0.0115:0.0293:0.157578:46368:rs7540009
1   1060608 rs17160824  G   A   .   PASS    .   ES:SE:LP:SS:ID  0.0048:0.0086:0.242376:46368:rs17160824
1   1061115 rs17160826  T   C   .   PASS    .   ES:SE:LP:SS:ID  0.0091:0.0091:0.502241:46368:rs17160826