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Table 2 Penetrance estimation for the present case studies

From: Calculating variant penetrance from family history of disease and average family size in population-scale data

Case study a

Data subset

Variant frequency in state (standard error)

Average sibship size

Residual disease risk a

States modelled c

Familial disease rate for people with variant across states modelled (95% CI)

Penetrance (95% CI)e

Familial

Sporadic

Unaffected

Assuming no residual disease risk

Accounting for residual disease risk

-

-

\({M}_{F} ({\sigma }_{\overline{{M }_{F}} })\)

\({M}_{S} ({\sigma }_{\overline{{M }_{S}}})\)

\({M}_{U}({\sigma }_{\overline{{M }_{U}}})\)

\(N\)

\(g\)

-

\(R(X)\)

\(f (g=0)\)

\(f (g=g)\)

LRRK2

p.G2019S for PD [26, 27]

European ancestry

0.033 (2.92 × 10–3)

0.012 (1.04 × 10–3)

4.67 × 10–4 (1.47 × 10–4)

1.572b.1

0.0267

F, S, U

0.113 (0.071, 0.155)

0.37 (0.285, 0.443)

0.334 (0.249, 0.408)

F, S

0.247 (0.202, 0.292)

0.429 (0.348, 0.509)

0.379 (0.299, 0.461)

F, U

0.172 (0.081, 0.264)

0.35 (0.247, 0.428)

0.32 (0.215, 0.399)

S, U

0.388 (0.235, 0.541)d

0.293 (0.161, 0.45)

0.275 (0.138, 0.438)

BMPR2 variants for PAH

All variants [17]

0.818 (0.025)

0.170 (0.011)

-

1.543b.2

0.0401

F, S

0.218 (0.195, 0.242)

0.382 (0.339, 0.426)

0.308 (0.266, 0.351)

All variants [30]

0.690 (0.061)

0.206 (0.036)

-

1.543b.2

0.0388

F, S

0.163 (0.111, 0.215)

0.281 (0.186, 0.376)

0.212 (0.12, 0.305)

SNVs and indels [30]

0.569 (0.065)

0.159 (0.033)

-

1.543b.2

0.0413

F, S

0.173 (0.107, 0.238)

0.299 (0.179, 0.419)

0.225 (0.11, 0.342)

Structural variants [30]

0.121 (0.043)

0.048 (0.019)

-

1.543b.2

0.0475

F, S

0.129 (0.011, 0.246)

0.218 (0.014, 0.432)

0.138 (0, 0.345)

SOD1 variants for ALS [35]

Asian

0.300 (0.025)

0.015 (2.55 × 10–3)

-

1.823b.3

0.00243

F, S

0.513 (0.420, 0.606)

0.829 (0.665, 1)

0.826 (0.661, 1)

European

0.148 (0.017)

0.012 (2.55 × 10–3)

-

1.543b.2

0.00245

F, S

0.394 (0.281, 0.506)

0.705 (0.496, 0.933)

0.701 (0.491, 0.926)

C9orf72RE for ALS [34]

Asian

0.04 (0.010)

0.01 (5.10 × 10–3)

-

1.823b.3

0.00247

F, S

0.174 (0.013, 0.335)

0.263 (0.0156, 0.522)

0.258 (0.0108, 0.518)

European

0.32 (0.020)

0.05 (5.10 × 10–3)

-

1.543b.2

0.00234

F, S

0.252 (0.208, 0.296)

0.443 (0.363, 0.524)

0.439 (0.358, 0.52)

  1. aDisease characteristics of lifetime disease risk (\(P{\left(A\right)}_{pop}\)) and proportion familial (\(P(F|A)\)(F|A)) are used as weighting factors (per Table 1) and for calculating \(g\) (per Eqs. (9–11), letting \(M_{U}=0\) in the ALS and PAH case studies), and are defined as follows: in PD, \(P{\left(A\right)}^{pop}=0.027,P\left(F|A\right)=0.105\); in PAH, \(P{\left(A\right)}^{pop}=0.05,P\left(F|A\right)=0.055\); in ALS, \(P{\left(A\right)}^{pop}=0.0025,P\left(F|A\right)=0.050\). bEstimated using Total Fertility Rates reported for the: populations sampled to calculate variant frequencies (see Additional File 1: Table S1) b.1, European Unionb.2, or East Asia and Pacificb.3 regions in 2018 [22]; cF = familial, S = sporadic, U = unaffected (controls); dRate of sporadic disease has been calculated here because the familial state is not represented; eStep 4 penetrance estimates are presented, see Additional File 1: Table S5 for unadjusted penetrance estimates derived in Step 3. PD, Parkinson’s disease; PAH, pulmonary arterial hypertension; ALS, amyotrophic lateral sclerosis; C9orf72RE, the pathogenic C9orf72 GGGGCC hexanucleotide repeat expansion; SNV, single nucleotide variant; indel, small insertions or deletions; CI, confidence interval
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